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Pulmonary embolism – An EFIM guideline critical appraisal and adaptation for practicing clinicians

Published:December 11, 2021DOI:https://doi.org/10.1016/j.ejim.2021.12.001

      Highlights

      • This EFIM guideline on pulmonary embolism adapts recommendations from existing CPGs. There were critical appraisal and adaptation of updated guidelines.
      • It is useful to assist physicians in decision making of specific/complex scenarios.
      • 35 recommendations on pulmonary embolism were endorsed for practicing clinicians.

      Abstract

      Background

      Several trials have been conducted in the last decades that challenged the management of patients with acute pulmonary embolism (PE) in terms of diagnosis and treatment. Updated international clinical practice guidelines (CPGs) endorsed the evidence from these trials. The aim of this document was to adapt recommendations from existing CPGs to assist physicians in decision making concerning specific and complex scenarios related to acute PE.

      Methods

      The flow for the adaptation procedure was first the identification of unsolved clinical issues in patients with acute PE (PICOs), then critically appraise the existing CPGs and choose the recommendations, which are the most applicable to these specific and complex scenarios.

      Results

      Five PICOs were identified and CPGs appraisal was performed. Concerning diagnosis of PE when computed tomographic pulmonary angiography is not available/contraindicated and d-dimer is less specific, perfusion lung scan is the preferred option in the majority of clinical scenarios. For the treatment of PE when relevant clinical conditions like pregnancy or severe renal failure are present heparin is to be used. Poor evidence and low-level recommendations exist on the best bleeding prediction rule in patients treated for PE. The duration of anticoagulation needs to be tailored concerning the presence of predisposing factors for index PE and the consequent risk for recurrence. Finally, recommendations on the opportunity to screen for cancer and thrombophilia patients without recognized thrombosis risk factors for PE are reported. Overall, 35 recommendations were endorsed and the rationale for the selection is reported in the main text.

      Conclusion

      By the use of proper methodology for the adaptation process, this document offers a simple and updated guide for practicing clinicians dealing with complex patients.

      Keywords

      1. Introduction

      Pulmonary embolism (PE) is the third most common cardiovascular disease with an incidence of 100–200 cases per 100,000 population per year. Moreover, the incidence rates of PE have been increasing around the world in last years [
      • Konstantinides S.V.
      • Barco S.
      • Lankeit M.
      • Meyer G.
      Management of pulmonary embolism: an update.
      ]. It is estimated that 1–2% of hospitalized patients experience PE [
      • Raskob G.E.
      • Angchaisuksiri P.
      • Blanco A.N.
      • Buller H.
      • Gallus A.
      • Hunt B.J.
      • et al.
      Thrombosis: a major contributor to global disease burden.
      ].
      The risk of suffering a PE doubles with each additional decade of life after age of 40, albeit as a common emergency with a potentially fatal outcome, it is affecting all ranges of patients across all ages [
      • Barco S.
      • Mahmoudpour S.H.
      • Valerio L.
      • Klok F.A.
      • Münzel T.
      • Middeldorp S.
      • et al.
      Trends in mortality related to pulmonary embolism in the European Region, 2000-15: analysis of vital registration data from the WHO Mortality Database.
      ]. Similarly, the impact of PE-related morbidity is crucial, including chronic thromboembolic pulmonary hypertension (pH) [
      • Janata K.
      • Holzer M.
      • Domanovits H.
      • Müllner M.
      • Bankier A.
      • Kurtaran A.
      • et al.
      Mortality of patients with pulmonary embolism.
      ].
      In Europe, an estimated 370,000 people die from acute PE each year. Up to 90% of deaths associated with this disease occur within two hours of symptom onset [
      • Wendelboe A.M.
      • Raskob G.E.
      Global burden of thrombosis: epidemiologic aspects.
      ]. Based on an analysis of the WHO registry data from Eastern, Western, Northern and Southern Europe, and Central Asia (2000 to 2015), the mortality due to PE was listed as one of the main causes of death according to ICD-10 [
      • Heit J.A.
      Epidemiology of venous thromboembolism.
      ].
      Several trials have been conducted in the last 2 decades that challenged the management of patients with acute PE in terms of diagnosis and treatment. Evidence from these trials have been endorsed by international societies that released updated guidelines for the management of patients with acute PE.
      Translating this data into everyday clinical care, PE represents a challenge for practicing clinicians, who often consult old patients, affected by a number of comorbidities. This can make clinical decision making cumbersome in terms of diagnosis and treatment approach.
      The aim of this document was to adapt recommendations from existing CPGs to assist physicians in specific and complex scenarios related to acute PE. The flow for the adaptation procedure was to identify unsolved clinical issues in patients suffering from PE, critically appraise the existing CPGs and choose the recommendations, which are the most applicable to the clinical practice.

      2. Methods

      To accomplish the European Federation of Internal Medicine (EFIM) objectives to get a reliable guideline dedicated to assisting clinicians in providing appropriate care for patients with acute PE in complex scenarios, we followed the methodology elaborated by the EFIM CPG working group (WG) [
      • Leśniak W.
      • Morbidoni L.
      • Dicker D.
      • Marín-León I.EFIM
      Clinical practice guidelines adaptation for internists - an EFIM methodology.
      ]. In summary, this extensive consensus and review process is composed of three phases: preparation, adaptation, and dissemination.

      2.1 Preparation phase

      The EFIM CPG-WG identified the topic “pulmonary embolism” as an issue for practicing clinicians and appointed the members of the pulmonary embolism task force (PE-TF) according to the previously defined structure: the chairperson of the CPG-WG (DD), two co-chairs of the PE-TF (VAK, CB), six CPG-WG members (WL, EB, IM, LM, FJM, AMM) and one external expert in the field of PE (ARM).

      2.2 Adaptation phase

      2.2.1 Define the clinical questions

      To select the clinical PICO (population, intervention, comparison and outcomes) questions to be included in the guideline we performed a survey distributed by e-mail and through the EFIM website among European internists asking about the most difficult issues and challenges in management (diagnosis, risk stratification, treatment, and follow-up) of patients with acute PE in their clinical practice.
      In the second phase, the final PICOs were selected in an internal consensus process based on their clinical relevance to everyday practice.

      2.2.2 Search, screen, and select guidelines used for adaptation

      Relevant documents (published in the last 5 years) were searched, using MEDLINE, Embase and Scopus databases. Details on search strategy are presented in Supplementary Material (annex 1). After duplicate removal, full-text documents were assessed for eligibility (CPG addressing one of the PICOs) by at least two authors (WL and AMM [PICO 1 and 3], IM, ARM and EB [PICO 2]; CB and VAK [PICO 4], LM and FJM [PICO 5]. Any discrepancies between evaluators during the study selection process were resolved by consensus of the PE-TF in a face-to-face meeting.

      2.2.3 Selection and assessment of good quality and updated evidence-based-CPG to include for adaptation

      The quality of included CPG on PE was independently assessed by four members of the PE-TF (WL, IM, LM, FJM) using the AGREE-II Instrument score [
      • Atkins D.
      • Best D.
      • Briss P.A.
      • Eccles M.
      • Falck-Ytter Y.
      • Flottorp S.
      • GRADE Working Group
      • et al.
      Grading quality of evidence and strength of recommendations.
      ] for Domain 1 (Scope and Purpose) and Domain 3 (Rigour of Development). A CPG was included if: a) the mean score was at least 3 for each item (i.e. at least 9 in Domain 1 and at least 24 in Domain 3; (b) at least 50% threshold for each of the maximum possible score for each of these two domains was reached. We also included the updated version of the selected CPGs when published or in press in the interim before the publication of this manuscript.

      2.2.4 Selecting recommendations from the existing original CPGs

      Within the PE-TF, different PICO teams (one for each PICO) of 2–3 panellists were formed. The choice and development of recommendations were made in a triple-round process.
      In the first of these rounds, each panelist independently identified the recommendations addressing the PICOs in the included CPGs and adapted this recommendation following the GRADE format for the quality of the evidence and the strength of the recommendation [
      AGREE Next Steps Consortium
      The AGREE II Instrument.
      ] (see Table 1), also integrating the information from the different CPGs that address the clinical question. In the second round, the panellists of each PICO team resolved discrepancies in the conflicting recommendations. In a third face-to-face meeting, all the members of the PE-TF resolved any left discrepancies and approved by consensus the final recommendations.
      Table 1Interpretation of the recommendation strength and quality of evidence.
      Interpretation of the quality of evidence
      Balshem et al. Journal of Clinical Epidemiology, 2011; 64: 401–406.
      Quality levelDefinition
      HighWe are very confident that the true effect lies close to that of the estimate of the effect.
      ModerateWe are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
      LowOur confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
      Very lowWe have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
      Interpretation of the strength of recommendation
      Andrews J. et al. Journal of Clinical Epidemiology, 2013; 66: 719–725.
      Strong recommendation

      Weak/conditional recommendation
      wording used in various documents to indicate the strength of recommendationsis recommended/is not recommended

      should be used/ should not be used/ must not be used
      is suggested to/ is suggested not to

      should be considered/ may be considered
      implication for patientsMost individuals in this situation would want the recommended course of action, and only a small proportion would not.The majority of individuals in this situation would want the suggested course of action, but many would not.
      implication for cliniciansMost individuals should follow the recommended course of action.

      Different choices will be appropriate for individual patients; clinicians must help each patient arrive at a management decision consistent with his or her values and preferences.
      Note: good practice statement is formulated if evidence is lacking, it is not possible to formulate the formal recommendation and the advice is based on expert opinion only.
      a Balshem et al. Journal of Clinical Epidemiology, 2011; 64: 401–406.
      b Andrews J. et al. Journal of Clinical Epidemiology, 2013; 66: 719–725.

      2.3 Dissemination phase

      Finally, PE-TF elaborated and approved by consensus a draft of the document that afterward was validated by two external experts in guidelines and PE, and the EFIM board to be published and disseminated.

      3. Results

      Between 13 Jan and 01 Mar 2020, 281 responses to the survey on relevant issues in the management of patients with acute PE were received from European internists and 20 most often mentioned clinical questions were selected. During two meetings of the PE-TF, a shorter list of 5 specific clinical questions with a PICO structure was agreed upon by consensus based on the 20 clinical questions suggested by the European internists (Table 2). The literature search performed between October 1 and 8, 2020 identified 3298 documents. After screening and exclusion of duplicates, 130 full texts articles remained that were independently evaluated by at least two members of the PE-FT. Twenty CPGs on PE were selected for quality assessment by AGREE-II instrument, and 10 were finally included to address the 5 PICOs of this guideline (Fig. 1: flowchart).
      Table 2List of PICOs.
      1. How to rule out PE if CT pulmonary angiography is not available or rises risks due to contrast medium administration and radiation exposure in a population where d-dimer is unreliable (CKD, pregnancy)?
      2. How to treat patients with PE and relevant clinical conditions?
      3. Which is the most accurate bleeding prediction rule in a comorbid patient treated for PE?
      4. What should be the duration of anticoagulation after PE (including special populations)?
      5. Do we need the screening for cancer and thrombophilia in PE patients without recognized thrombosis risk factors?
      CKD – chronic kidney disease, CT – computer tomography, PE – pulmonary embolism, VTE – venous thromboembolism.
      Fig. 1
      Fig. 1flowchart of the clinical practice guidelines (CPGs) selection process, following the PRISMA statement [Moher 2009].
      PICO #1: How to rule out PE if computed tomographic pulmonary angiography (CTPA) is not available or rises risks due to contrast medium administration and radiation exposure in a population where D-dimer is unavailable or less specific (severe chronic kidney disease (CKD), pregnancy)?
      D-dimer should be used to select patients with low or intermediate pre-test probability of PE that should proceed to CTPA. Unfortunately, in some patients with suspected PE D-dimer results are less specific (e.g. severe CKD or pregnancy) and CTPA is not available or rises safety concerns. Among the selected CPGs, four address this clinical question [
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ,
      • Lim W.
      • Le Gal G.
      • Bates S.M.
      • Righini M.
      • Haramati L.B.
      • Lang E.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism.
      ,
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ]. Three scenarios were discussed by the CPGs: 1) contrast induced allergy; 2) CKD; 3) pregnancy. Contrast induced allergy and CKD were discussed together whereas pregnancy was considered as an isolated issue. Suspicion of PE is taken based on clinical prediction scores.

      3.1 Contrast induced allergy and renal impairment

      1.1. Ventilation/perfusion (V/Q) lung scanning is largely suggested by the three guidelines [
      • Atkins D.
      • Best D.
      • Briss P.A.
      • Eccles M.
      • Falck-Ytter Y.
      • Flottorp S.
      • GRADE Working Group
      • et al.
      Grading quality of evidence and strength of recommendations.
      ,
      AGREE Next Steps Consortium
      The AGREE II Instrument.
      ,
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ] in case of known contrast induced allergy or severe CKD, or if CTPA is unavailable. Weak, Quality of Evidence (QoE): low/moderate.
      1.2. In patients with low or intermediate prevalence/pretest probability (PTP) it is suggested to use V/Q scan. No further examinations are usually needed in patients with negative/normal V/Q scan. However, in the population with high prevalence/PTP (≥50%) the V/Q scan may be acceptable if non-diagnostic scans are followed by additional testing, such as CTPA and/or proximal ultrasound of the lower extremities [
      • Lim W.
      • Le Gal G.
      • Bates S.M.
      • Righini M.
      • Haramati L.B.
      • Lang E.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism.
      ]. Weak, QoE: low.
      If additional tests cannot be done immediately, therapeutic anticoagulation should be offered to patients with high prevalence/PTP (≥50%) and non-diagnostic V/Q scan [
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ].
      It is necessary to remark that V/Q scan is unavailable in many clinical settings. In such cases, other diagnostic tests (see 1.3, 1.4, and 1.5) may help in differential diagnosis.
      1.3. In the emergency department setting, using PE rule-out criteria (PERC) can be applied to determine whether patients with a low probability of PE are likely or unlikely to have PE and whether additional diagnostic testing with D-dimer is warranted. Weak, QoE: low/moderate [
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ].
      Comment: PERC is a validated tool to rule out PE in the population of low PE probability [
      • Kline J.A.
      • Mitchell A.M.
      • Kabrhel C.
      • Richman P.B.
      • Courtney D.M.
      Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism.
      ,
      • Kline J.A.
      • Courtney D.M.
      • Kabrhel C.
      • Moore C.L.
      • Smithline H.A.
      • Plewa M.C.
      • et al.
      Prospective multicenter evaluation of the pulmonary embolism rule-out criteria.
      ,
      • Penaloza A.
      • Soulié C.
      • Moumneh T.
      • Delmez Q.
      • Ghuysen A.
      • El Kouri D.
      • et al.
      Pulmonary embolism rule-out criteria (PERC) rule in European patients with low implicit clinical probability (PERCEPIC): a multicentre, prospective, observational study.
      ,
      • Freund Y.
      • Cachanado M.
      • Aubry A.
      • Orsini C.
      • Raynal P.A.
      • Féral-Pierssens A.L.
      • et al.
      Effect of the pulmonary embolism rule-out criteria on subsequent thromboembolic events among low-risk emergency department patients: the PROPER Randomized Clinical Trial.
      ]. The PERC rule negative requires age <50 years, pulse <100 beats/min, pulse oximetry ≥95%, no unilateral leg swelling, no haemoptysis, no surgery/trauma requiring hospitalization within 4 weeks, no prior PE or DVT, and no estrogen use.
      1.4. For patients with suspected PE in whom diagnostic imaging is required, a baseline chest radiogram might identify an alternate diagnosis to account for the patient's symptoms and potentially avoid further diagnostic imaging [
      • Lim W.
      • Le Gal G.
      • Bates S.M.
      • Righini M.
      • Haramati L.B.
      • Lang E.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism.
      ]. Good practice statement.

      Comment: however, it must be noted that such situation is rare.

      1.5. Bedside transthoracic echocardiography (TTE or point-of-care ultrasound (POCUS)) should be performed in patients with suspected PE and hemodynamical instability and if right ventricular dysfunction is present but CTPA is not available, patients should be immediately referred for reperfusion strategies [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ]. Strong, QoE: very low.
      Comment: TTE has a negative predictive value for PE diagnosis ranging from 40 to 50% [
      • Dabbouseh N.M.
      • Patel J.J.
      • Bergl P.A.
      Role of echocardiography in managing acute pulmonary embolism.
      ]. Although its limited specificity it can be particularly helpful when no other test is available, since it allows to exclude other causes of heart dysfunction (acute left ventricular dysfunction, tamponade, acute valvular disease, aortic dissection).
      1.6. Compression ultrasonography (CUS) it is recommended to accept the diagnosis of VTE (and PE) if a CUS shows a proximal deep vein thrombosis in a patient with clinical suspicion of PE [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ]. Strong, QoE: high.
      Comment: The CUS is helpful in patients with suspicion of PE which can performed after using the clinical prediction scales and if available additional tests (biomarkers, TTE) are available.

      3.2 Pregnancy

      1.7. In case of pregnancy V/Q lung scanning (if available) should be preferred [
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ] to CTPA if a low radiation protocol is not available [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ]. Weak, QoE: low.
      Comment: Pregnancy-Adapted YEARS algorithm to rule out the diagnosis of suspected PE allowing to adapt the d-dimer levels in this population was developed and validated [
      • van der Pol L.M.
      • Tromeur C.
      • Bistervels I.M.
      • Ni Ainle F.
      • van Bemmel T.
      • Bertoletti L.
      • Artemis Study Investigators
      • et al.
      Pregnancy-adapted YEARS algorithm for diagnosis of suspected pulmonary embolism.
      ].
      1.8. A CTPA with a low-radiation dose protocol or perfusion scintigraphy should be considered to rule-out PE [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ]. Weak, QoE: very low.
      1.9. In a pregnant patient with suspected PE (particularly if she has symptoms of DVT), venous CUS may be considered to avoid unnecessary irradiation [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ]. Weak, QoE: moderate.
      PICO #2: How to treat patients with PE and relevant clinical conditions?

      3.3 How to treat patients with PE and cancer?

      Eight of the updated CPGs selected for this adaptation document address this clinical question [
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ,
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ,
      • Lyman G.H.
      • Carrier M.
      • Ay C.
      • Di Nisio M.
      • Hicks L.K.
      • Khorana A.A.
      • et al.
      American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer.
      ,
      • Farge D.
      • Frere C.
      • Connors J.M.
      • Ay C.
      • Khorana A.A.
      • Munoz A.
      • et al.
      2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.
      ,
      • Key N.S.
      • Khorana A.A.
      • Kuderer N.M.
      • Bohlke K.
      • Lee A.Y.Y.
      • Arcelus J.I.
      • et al.
      Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update.
      ,
      • Howard L.S.
      • Barden S.
      • Condliffe R.
      • Connolly V.
      • Davies C.
      • Donaldson J.
      • et al.
      British Thoracic Society Guideline for the initial outpatient management of pulmonary embolism.
      ,
      • Stevens S.M.
      • Woller S.C.
      • Baumann Kreuziger L.
      • Bounameaux H.
      • Doerschug K.
      • Geersing G.J.
      • et al.
      Executive Summary: antithrombotic Therapy for VTE Disease: second Update of the CHEST Guideline and Expert Panel Report.
      ]. In these CPGs five specific clinical scenarios were considered: a) Initial treatment of confirmed PE in patients with cancer; b) Outpatient (OP) management of the PE patient with cancer; c) Early maintenance (up to 6 months) and long-term treatment (beyond 6 months); d) Treatment of PE recurrence in patients with cancer under anticoagulation; e) Other special situations.

      3.4 Initial treatment of confirmed PE

      2.1. It is suggested to use DOAC (apixaban, edoxaban or rivaroxaban) or LMWH for initial treatment of VTE in patients with cancer [
      • Lyman G.H.
      • Carrier M.
      • Ay C.
      • Di Nisio M.
      • Hicks L.K.
      • Khorana A.A.
      • et al.
      American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer.
      ] Strong, QoE: moderate.
      Comment: For gastrointestinal luminal cancer with high bleeding risk there are strong evidence that apixaban is a safe treatment.
      2.2. It is recommended to use LMWH over UFH for initial treatment of VTE in patients with cancer [
      • Lyman G.H.
      • Carrier M.
      • Ay C.
      • Di Nisio M.
      • Hicks L.K.
      • Khorana A.A.
      • et al.
      American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer.
      ]. Strong, QoE: moderate.
      2.3. It is suggested to use LMWH over fondaparinux for initial treatment of VTE in patients with cancer [
      • Lyman G.H.
      • Carrier M.
      • Ay C.
      • Di Nisio M.
      • Hicks L.K.
      • Khorana A.A.
      • et al.
      American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer.
      ]. Weak, QoE: very low.
      2.4. Thrombolysis can be considered on a case-by-case basis in hemodynamically unstable PE patients, with specific attention to contraindications, especially bleeding risk – e.g. brain metastasis [
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ,
      • Farge D.
      • Frere C.
      • Connors J.M.
      • Ay C.
      • Khorana A.A.
      • Munoz A.
      • et al.
      2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.
      ,
      • Key N.S.
      • Khorana A.A.
      • Kuderer N.M.
      • Bohlke K.
      • Lee A.Y.Y.
      • Arcelus J.I.
      • et al.
      Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update.
      ,
      • Howard L.S.
      • Barden S.
      • Condliffe R.
      • Connolly V.
      • Davies C.
      • Donaldson J.
      • et al.
      British Thoracic Society Guideline for the initial outpatient management of pulmonary embolism.
      ,
      • Stevens S.M.
      • Woller S.C.
      • Baumann Kreuziger L.
      • Bounameaux H.
      • Doerschug K.
      • Geersing G.J.
      • et al.
      Executive Summary: antithrombotic Therapy for VTE Disease: second Update of the CHEST Guideline and Expert Panel Report.
      ,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ]. Weak, QoE: low.
      Comment: Patients should be treated with full anticoagulation and monitored for evidence of clinical deterioration. Such deterioration should prompt consideration of thrombolytic therapy in the absence of shock if the bleeding risk is deemed acceptable [
      • Stevens S.M.
      • Woller S.C.
      • Baumann Kreuziger L.
      • Bounameaux H.
      • Doerschug K.
      • Geersing G.J.
      • et al.
      Executive Summary: antithrombotic Therapy for VTE Disease: second Update of the CHEST Guideline and Expert Panel Report.
      ]. An alternative in patients with high bleeding risk (see recommendation 2.5).
      2.5. In patients with acute PE associated with hypotension who also have (i) a high bleeding risk, (ii) failed systemic thrombolysis, or (iii) shock that is likely to cause death before systemic thrombolysis can take effect (e.g., within hours), if appropriate expertise and resources are available, it is suggested catheter-assisted thrombus removal over no such intervention [
      • Stevens S.M.
      • Woller S.C.
      • Baumann Kreuziger L.
      • Bounameaux H.
      • Doerschug K.
      • Geersing G.J.
      • et al.
      Executive Summary: antithrombotic Therapy for VTE Disease: second Update of the CHEST Guideline and Expert Panel Report.
      ]. WeaK, QoE: low.

      3.5 Primary treatment (up to 6 months) and secondary prevention (beyond 6 months)

      2.6. DOAC (preferred) or LMWH should be used for a minimum of 6 months to treat established PE in patients with cancer when creatinine clearance is ≥30 mL/min [
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ,
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ,
      • Lyman G.H.
      • Carrier M.
      • Ay C.
      • Di Nisio M.
      • Hicks L.K.
      • Khorana A.A.
      • et al.
      American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer.
      ,
      • Farge D.
      • Frere C.
      • Connors J.M.
      • Ay C.
      • Khorana A.A.
      • Munoz A.
      • et al.
      2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.
      ,
      • Key N.S.
      • Khorana A.A.
      • Kuderer N.M.
      • Bohlke K.
      • Lee A.Y.Y.
      • Arcelus J.I.
      • et al.
      Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update.
      ,
      • Stevens S.M.
      • Woller S.C.
      • Baumann Kreuziger L.
      • Bounameaux H.
      • Doerschug K.
      • Geersing G.J.
      • et al.
      Executive Summary: antithrombotic Therapy for VTE Disease: second Update of the CHEST Guideline and Expert Panel Report.
      ]. Strong, QoE: high. For patients with gastrointestinal neoplasm and high bleeding risk, apixaban is considered a safe treatment [
      • Stevens S.M.
      • Woller S.C.
      • Baumann Kreuziger L.
      • Bounameaux H.
      • Doerschug K.
      • Geersing G.J.
      • et al.
      Executive Summary: antithrombotic Therapy for VTE Disease: second Update of the CHEST Guideline and Expert Panel Report.
      ]. Strong, QoE: moderate
      2.7. Beyond the initial 6 months, extended anticoagulant therapy (no scheduled stop date) should be considered in selected patients (i.e. active cancer or with metastatic disease or receiving chemotherapy). Termination or continuation of anticoagulation should be based on individual evaluation [
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ,
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ,
      • Lyman G.H.
      • Carrier M.
      • Ay C.
      • Di Nisio M.
      • Hicks L.K.
      • Khorana A.A.
      • et al.
      American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer.
      ,
      • Farge D.
      • Frere C.
      • Connors J.M.
      • Ay C.
      • Khorana A.A.
      • Munoz A.
      • et al.
      2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.
      ,
      • Key N.S.
      • Khorana A.A.
      • Kuderer N.M.
      • Bohlke K.
      • Lee A.Y.Y.
      • Arcelus J.I.
      • et al.
      Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update.
      ]. Weak, QoE: very low.
      2.8. In the event of PE recurrence, after assessing bleeding risk with a validated score, consider to: 1) for LMWH, increase the dose [
      • Key N.S.
      • Khorana A.A.
      • Kuderer N.M.
      • Bohlke K.
      • Lee A.Y.Y.
      • Arcelus J.I.
      • et al.
      Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update.
      ] by 20–25% [
      • Farge D.
      • Frere C.
      • Connors J.M.
      • Ay C.
      • Khorana A.A.
      • Munoz A.
      • et al.
      2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.
      ,
      • Stevens S.M.
      • Woller S.C.
      • Baumann Kreuziger L.
      • Bounameaux H.
      • Doerschug K.
      • Geersing G.J.
      • et al.
      Executive Summary: antithrombotic Therapy for VTE Disease: second Update of the CHEST Guideline and Expert Panel Report.
      ] or switch to DOACs; 2) for DOACs, switch to LMWH; 3) for Vitamin K antagonists (VKA), switch to LMWH or DOACs. If anticoagulant intensity cannot be increased because the risk of bleeding, an inferior vena cava filter may be inserted as a last resort to prevent PE [
      • Farge D.
      • Frere C.
      • Connors J.M.
      • Ay C.
      • Khorana A.A.
      • Munoz A.
      • et al.
      2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.
      ,
      • Key N.S.
      • Khorana A.A.
      • Kuderer N.M.
      • Bohlke K.
      • Lee A.Y.Y.
      • Arcelus J.I.
      • et al.
      Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update.
      ,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ]. Weak, QoE: low.

      3.6 How to treat patients with PE and severe CKD?

      Four of the selected updated CPGs address this clinical question [
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ,
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Farge D.
      • Frere C.
      • Connors J.M.
      • Ay C.
      • Khorana A.A.
      • Munoz A.
      • et al.
      2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.
      ,
      • Key N.S.
      • Khorana A.A.
      • Kuderer N.M.
      • Bohlke K.
      • Lee A.Y.Y.
      • Arcelus J.I.
      • et al.
      Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update.
      ]. There is complete agreement across all the CPGs.
      2.9. In severe CKD (creatinine clearance <30 mL/min), for PE treatment it is suggested to use unfractionated heparin (UFH) followed by early VKA or adjusted doses of LMWH to anti-FXa level with the institutional standard available [
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ,
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Farge D.
      • Frere C.
      • Connors J.M.
      • Ay C.
      • Khorana A.A.
      • Munoz A.
      • et al.
      2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.
      ,
      • Key N.S.
      • Khorana A.A.
      • Kuderer N.M.
      • Bohlke K.
      • Lee A.Y.Y.
      • Arcelus J.I.
      • et al.
      Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update.
      ]. Weak, QoE: low.
      Comment: Although the concordance between the most used formulas to assess CKD, the Cockcroft and Gault (CG) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), is less than perfect, the rate of major bleeding is similarly identifying irrespective of the formula used.

      3.7 How to treat patients with PE and pregnancy?

      Two of the selected CPGs address this clinical question [
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Howard L.S.
      • Barden S.
      • Condliffe R.
      • Connolly V.
      • Davies C.
      • Donaldson J.
      • et al.
      British Thoracic Society Guideline for the initial outpatient management of pulmonary embolism.
      ]. In these CPGs 3 specific clinical scenarios were considered: a) Treatment of PE in pregnant women; b) Management of anticoagulants around the time of delivery; c) Anticoagulant use in breastfeeding women with PE. Only the first scenario applies to internal medicine practice.
      2.10. LMWH is recommended over UFH. UFH is recommended in patients who may require thrombolysis, surgery or urgent delivery [
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Howard L.S.
      • Barden S.
      • Condliffe R.
      • Connolly V.
      • Davies C.
      • Donaldson J.
      • et al.
      British Thoracic Society Guideline for the initial outpatient management of pulmonary embolism.
      ]. Strong, QoE: low/moderate.
      DOACs or VKAs should not be used in pregnant patients.
      LMWH: it is recommended not to use the monitoring of anti-FXa levels.

      3.8 How to treat patients with PE and thrombocytopenia?

      Two CPGs evaluated (one fulfilling and one not fulfilling quality criteria) address indirectly this clinical question [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ,
      • Napolitano M.
      • Saccullo G.
      • Marietta M.
      • Carpenedo M.
      • Castaman G.
      • Cerchiara E.
      • et al.
      Platelet cut-off for anticoagulant therapy in thrombocytopenic patients with blood cancer and venous thromboembolism: an expert consensus.
      ]. The recommendations are from two expert consensuses in cancer patients, although it could be applied to non-cancer patients too.
      2.11. Expert consensus suggests to guide decision with the following platelet count thresholds:
      • 1)
        >50 × 109/L: Therapeutic dose of anticoagulants;
      • 2)
        30–50 × 109/L: 50% dose of anticoagulants;
      • 3)
        <30 × 109/L: Discontinuation or prophylactic dose ± inferior vena cava filter ± platelet transfusion [
        • Konstantinides S.V.
        • Meyer G.
        • Becattini C.
        • Bueno H.
        • Geersing G.J.
        • Harjola
        • et al.
        2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
        ,
        • Napolitano M.
        • Saccullo G.
        • Marietta M.
        • Carpenedo M.
        • Castaman G.
        • Cerchiara E.
        • et al.
        Platelet cut-off for anticoagulant therapy in thrombocytopenic patients with blood cancer and venous thromboembolism: an expert consensus.
        ]. Good Practice statement.

      3.9 How to treat patients with PE and anemia?

      Neither of the updated CPG evaluated and fulfilling quality criteria, nor the CPGs rated as not fulfilling the quality threshold address this clinical question.
      There are no specific recommendations for PE treatment in patients with anemia.
      Although anemia is included in some bleeding risk scores [
      • Di Nisio M.
      • Lee A.Y.
      • Carrier M.
      • Liebman H.A.
      • Khorana A.A.
      • Malignancy SoHa
      Diagnosis and treatment of incidental venous thromboembolism in cancer patients: guidance from the SSC of the ISTH.
      ,
      • Fang M.C.
      • Go A.S.
      • Chang Y.
      • Borowsky L.H.
      • Pomernacki N.K.
      • Udaltsova N.
      • et al.
      A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study.
      ,
      • Ruíz-Giménez N.
      • Suárez C.
      • González R.
      • Nieto J.A.
      • Todolí J.A.
      • Samperiz A.L.
      • et al.
      Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry.
      ], there are no specific recommendations about how to deal with these patients regarding anticoagulant treatment.
      We therefore identify a major gap in knowledge and a research recommendation. Studies addressing specific risk and management of anemic patients with PE are needed.
      PICO #3: Which are the best bleeding prediction rule in a comorbid patient treated for PE?
      The issue was addressed by four CPGs [
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ,
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ,
      • Ortel T.L.
      • Neumann I.
      • Ageno W.
      • Beyth R.
      • Clark N.P.
      • Cuker A.
      • et al.
      American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism.
      ]. In general, to date no prediction tool has been externally validated in such clinical situation. Further studies are needed. Bleeding scores should mainly be used to identify and treat reversible risk factors for bleeding, and to inform the decision on the extension and dose of anticoagulation beyond the first 3 months, which is the minimum treatment period recommended for all patients with PE. For this reason, specific indications are provided in two CPGs only [
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ].
      3.1. The proposed suggested option [
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ] is to use the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score for major bleeding risk assessment during anticoagulation treatment. However, the HAS-BLED accuracy has not been sufficiently proven in PE [
      • Klok F.A.
      • Niemann C.
      • Dellas C.
      • Hasenfuß G.
      • Konstantinides S.
      • Lankeit M.
      Performance of five different bleeding-prediction scores in patients with acute pulmonary embolism.
      ,
      • Kresoja K.P.
      • Ebner M.
      • Rogge N.I.J.
      • Sentler C.
      • Keller K.
      • Hobohm L.
      • et al.
      Prediction and prognostic importance of in-hospital major bleeding in a real-world cohort of patients with pulmonary embolism.
      ,
      • Kooiman J.
      • van Hagen N.
      • Iglesias Del Sol A.
      • Planken E.V.
      • Lip G.Y.
      • et al.
      The HAS-BLED score identifies patients with acute venous thromboembolism at high risk of major bleeding complications during the first six months of anticoagulant treatment.
      ,
      • Riva N.
      • Bellesini M.
      • Di Minno M.N.
      • Mumoli N.
      • Pomero F.
      • Franchini M.
      • et al.
      Poor predictive value of contemporary bleeding risk scores during long-term treatment of venous thromboembolism. A multicentre retrospective cohort study.
      ] to be used as the sole basis for the decision. Weak, QoE: low.
      3.2. A further risk stratification of major bleeding (MB) can be performed by assessing the prevalence of one of the following risk factors [
      • Stevens S.M.
      • Woller S.C.
      • Baumann Kreuziger L.
      • Bounameaux H.
      • Doerschug K.
      • Geersing G.J.
      • et al.
      Executive Summary: antithrombotic Therapy for VTE Disease: second Update of the CHEST Guideline and Expert Panel Report.
      ]: 1) age >75 years; 2) active cancer; 3) metastatic disease; 4) chronic renal or hepatic failure; 5) platelet count <80 × 109/L; 6) need for antiplatelet therapy; 7) history of bleeding without a reversible cause. Good practice statement.
      Comment: This score is likely to stratify patients in low risk (no risk factors: 0.8% annualized risk of MB), moderate risk (one bleeding risk factor: 1.6% annualized risk of MB) and high risk (≥2 bleeding risk factors: 6.5% annualized risk of MB). However, this score has shown insufficiently predictive value for bleeding in patients included in the Italian START2 Register [
      • Palareti G.
      • Antonucci E.
      • Mastroiacovo D.
      • Ageno W.
      • Pengo V.
      • Poli D.
      • et al.
      The American College of Chest Physician score to assess the risk of bleeding during anticoagulation in patients with venous thromboembolism.
      ]. Recently, a user-friendly score to estimate risk of early (30-days) major bleeding specifically in patients with acute PE has been developed [
      • Chopard R.
      • Piazza G.
      • Falvo N.
      • Ecarnot F.
      • Besutti M.
      • Capellier G.
      • et al.
      An original risk score to predict early major bleeding in acute pulmonary embolism: the syncope, anemia, renal dysfunction (PE-SARD) bleeding score.
      ].
      PICO #4: What should be the duration of anticoagulation after PE (including special populations)?
      Six of the updated CPGs fulfilling quality criteria and included in this appraisal address this clinical question [
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ,
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ,
      • Lyman G.H.
      • Carrier M.
      • Ay C.
      • Di Nisio M.
      • Hicks L.K.
      • Khorana A.A.
      • et al.
      American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer.
      ,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ,
      • Ortel T.L.
      • Neumann I.
      • Ageno W.
      • Beyth R.
      • Clark N.P.
      • Cuker A.
      • et al.
      American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism.
      ]. For this document, we adopt the wording of North American CPGs concerning the categorization of PE as provoked or unprovoked by any identifiable risk factors and concerning the identification of different phases of PE treatment as initial, primary (early maintenance), and extended (long-term, secondary prevention). In these CPGs 4 different clinical scenarios were considered: a) All PE patients (in general); b) PE provoked by a chronic risk factor; c) PE provoked by a transient risk factor; d) Unprovoked PE (without any identifiable risk factors). There is almost complete agreement across the included CPGs. Six of the selected CPGs also addressed the duration of anticoagulation after PE in special populations like patients with cancer associated venous thromboembolism (VTE), antiphospholipid antibody syndrome, pregnancy or contraceptives, chronic thromboembolic pulmonary hypertension [
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ,
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Lyman G.H.
      • Carrier M.
      • Ay C.
      • Di Nisio M.
      • Hicks L.K.
      • Khorana A.A.
      • et al.
      American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer.
      ,
      • Farge D.
      • Frere C.
      • Connors J.M.
      • Ay C.
      • Khorana A.A.
      • Munoz A.
      • et al.
      2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.
      ,
      • Key N.S.
      • Khorana A.A.
      • Kuderer N.M.
      • Bohlke K.
      • Lee A.Y.Y.
      • Arcelus J.I.
      • et al.
      Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update.
      ,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ]. Various definitions were used to identify different periods of PE treatment across different guidelines.
      Criteria, which influence the decision regarding the duration of anticoagulation after pulmonary embolism, are shown in Fig. 2.
      Fig. 2
      Fig. 2Duration of anticoagulation (AC) after pulmonary embolism (PE) in patients who completed primary treatment. Comment: For additional information, see the text.
      All most recent CPGs [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ,
      • Ortel T.L.
      • Neumann I.
      • Ageno W.
      • Beyth R.
      • Clark N.P.
      • Cuker A.
      • et al.
      American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism.
      ] recommend using DOACs over VKAs for the treatment of PE in patients without contraindications.

      3.10 All PE patients

      4.1. Therapeutic anticoagulation for at least three months is recommended for all patients with PE [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ]. Strong, QoE: high.
      4.2. For primary treatment of acute PE, shorter courses of anticoagulation (3–6 months) are suggested over longer courses (6–12 months) [
      • Ruíz-Giménez N.
      • Suárez C.
      • González R.
      • Nieto J.A.
      • Todolí J.A.
      • Samperiz A.L.
      • et al.
      Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry.
      ]. Weak, QoE: moderate.

      3.11 PE provoked by a chronic (non-cancer) risk factor

      4.3. Indefinite or extended antithrombotic therapy over stopping anticoagulation is suggested [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ,
      • Ortel T.L.
      • Neumann I.
      • Ageno W.
      • Beyth R.
      • Clark N.P.
      • Cuker A.
      • et al.
      American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism.
      ]. Weak, QoE: moderate.

      3.12 PE provoked by a transient risk factor

      4.4. Discontinuation of therapeutic oral anticoagulation is recommended after 3 months if PE is provoked by transient (temporary, removable) risk factors [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ,
      • Ortel T.L.
      • Neumann I.
      • Ageno W.
      • Beyth R.
      • Clark N.P.
      • Cuker A.
      • et al.
      American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism.
      ]. Strong, QoE: moderate.
      Comment: A distinction is suggested between PE provoked by major or minor transient risk factors. Patients suffering PE provoked by minor risk factors (minor surgery, admission to hospital for less than 3 days, estrogen therapy/contraception, pregnancy puerperium, confined to bed out of hospital for ≥3 days with an acute illness, leg injury (without fracture) associated with reduced mobility for ≥3 days, long haul flight) could be candidates for pharmacological strategies for secondary prevention of VTE [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ]. This decision should be balanced taking into account the risk of bleeding [
      • Ortel T.L.
      • Neumann I.
      • Ageno W.
      • Beyth R.
      • Clark N.P.
      • Cuker A.
      • et al.
      American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism.
      ]. Although no specific trial assessed this issue, evidence is available from subgroup of patients from randomized clinical trials and a meta-analysis showing different risk for recurrence in these patients.
      4.5. For patients with PE provoked by a transient risk factor who have a history of previous VTE:
      • (1)
        if previous VTE was unprovoked or provoked by a chronic risk factor, indefinite antithrombotic therapy is suggested [
        • Konstantinides S.V.
        • Meyer G.
        • Becattini C.
        • Bueno H.
        • Geersing G.J.
        • Harjola
        • et al.
        2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
        ,
        • Kearon C.
        • Akl E.A.
        • Ornelas J.
        • Blaivas A.
        • Jimenez D.
        • Bounameaux H.
        • et al.
        Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
        ,
        • Ortel T.L.
        • Neumann I.
        • Ageno W.
        • Beyth R.
        • Clark N.P.
        • Cuker A.
        • et al.
        American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism.
        ];
      • (2)
        if previous VTE was also provoked by a transient risk factor, stopping anticoagulation after completion of primary treatment is suggested [
        • Kearon C.
        • Akl E.A.
        • Ornelas J.
        • Blaivas A.
        • Jimenez D.
        • Bounameaux H.
        • et al.
        Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
        ,
        • Ortel T.L.
        • Neumann I.
        • Ageno W.
        • Beyth R.
        • Clark N.P.
        • Cuker A.
        • et al.
        American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism.
        ]. Weak, QoE: moderate.

      3.13 Unprovoked PE

      4.6. Extended oral anticoagulation of indefinite duration should be considered [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ,
      • Ortel T.L.
      • Neumann I.
      • Ageno W.
      • Beyth R.
      • Clark N.P.
      • Cuker A.
      • et al.
      American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism.
      ]. Weak, QoE: high. However, this recommendation does not apply to patients with high bleeding risk [
      • Fang M.C.
      • Go A.S.
      • Chang Y.
      • Borowsky L.H.
      • Pomernacki N.K.
      • Udaltsova N.
      • et al.
      A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study.
      ]. Weak, QoE: moderate.

      3.14 Duration of anticoagulation in special populations

      3.14.1 Cancer associated VTE

      Five of the selected updated CPGs address this clinical question [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ,
      • Lyman G.H.
      • Carrier M.
      • Ay C.
      • Di Nisio M.
      • Hicks L.K.
      • Khorana A.A.
      • et al.
      American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer.
      ,
      • Farge D.
      • Frere C.
      • Connors J.M.
      • Ay C.
      • Khorana A.A.
      • Munoz A.
      • et al.
      2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.
      ,
      • Key N.S.
      • Khorana A.A.
      • Kuderer N.M.
      • Bohlke K.
      • Lee A.Y.Y.
      • Arcelus J.I.
      • et al.
      Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update.
      ,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ]. There is complete agreement across all the CPGs. See recommendation 2.5.

      3.14.2 Antiphospholipid antibody syndrome

      Only two of the selected updated CPGs addresses this clinical question [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ].
      4.7. Oral anticoagulant treatment with VKAs for an indefinite period is recommended for patients with antiphospholipid antibody syndrome [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ]. Strong, QoE: moderate.

      3.15 Pregnancy and women on contraceptives

      Three of the selected updated CPGs address this clinical question [
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ].
      4.8. Anticoagulant treatment should be considered for ≥6 weeks after delivery and with a minimum overall treatment duration of 3 months [
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Stevens S.M.
      • Woller S.C.
      • Baumann Kreuziger L.
      • Bounameaux H.
      • Doerschug K.
      • Geersing G.J.
      • et al.
      Executive Summary: antithrombotic Therapy for VTE Disease: second Update of the CHEST Guideline and Expert Panel Report.
      ] Weak, QoE: low.
      4.9. In a young female suffering from acute PE while on oral estrogen-containing contraceptives it is suggested to discontinue hormonal contraceptives after discussing alternative methods of contraception; and consider discontinuing the anticoagulation after 3 months [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ,
      • Howard L.S.
      • Barden S.
      • Condliffe R.
      • Connolly V.
      • Davies C.
      • Donaldson J.
      • et al.
      British Thoracic Society Guideline for the initial outpatient management of pulmonary embolism.
      ]. Weak, QoE: low.
      4.10. In a young female suffering from acute PE while on other contraceptives it is suggested to manage chronic anticoagulation as an acute PE occurring in the absence of identifiable risk factors [
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola
      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
      ]. Weak, QoE: low.

      3.16 Chronic thromboembolic pulmonary hypertension

      Only one of the selected updated CPGs addresses this clinical question [
      • Stevens S.M.
      • Woller S.C.
      • Baumann Kreuziger L.
      • Bounameaux H.
      • Doerschug K.
      • Geersing G.J.
      • et al.
      Executive Summary: antithrombotic Therapy for VTE Disease: second Update of the CHEST Guideline and Expert Panel Report.
      ].
      4.11. Lifelong oral anticoagulation with VKAs is recommended, also after successful pulmonary endarterectomy or balloon pulmonary angioplasty [
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ]. Strong, QoE: low.
      PICO #5: Do we need the screening for cancer and thrombophilia in PE patients without recognized thrombosis risk factors?
      Only NICE guidelines [
      • McCormack T.
      • Harrisingh M.C.
      • Horner D.
      • Bewley S.
      • Committee G.
      Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing.
      ] address this question.

      3.17 Screening for cancer

      5.1. For people with unprovoked DVT or PE who are not known to have cancer, are recommended a limited screen of cancer (medical history, physical examination, full blood count, renal-hepatic function and PT-APTT). The extensive screen (CT scan) is only recommended in case of clinical symptoms or signs suggestive of cancer. Strong, QoE: low/moderate.
      Comment: No clear benefit of extensive strategies (including comprehensive imaging) compared to basic strategies (physical examination, blood tests, etc.) emerged in terms of multiples outcomes (detection of early-stage cancer, time to cancer diagnosis, all-cause mortality, cancer-related mortality).
      New data coming from ongoing studies hopefully available by the end of 2021 could help to address this issue. In particular, the following trials are worth mentioning: the trial Tumor-educated Platelets in Venous Thromboembolism (NCT02739867), evaluating the blood-based “liquid biopsies”, SOME RIETE (NCT03937583) and MVTEP2-SOME2 (NCT04304651) trials, both from the Riete Registry, evaluating CT/PET as extended strategy [
      • Marín-Romero S.
      • Jara-Palomares L.
      Screening for occult cancer: where are we in 2020?.
      ].

      3.18 Screening for thrombophilia

      5.2. For people who had provoked or unprovoked PE who are continuing anticoagulation treatment, it is suggested not to offer testing for hereditary thrombophilia. However, for people who have had unprovoked DVT/PE and who plan to stop anticoagulant treatment, testing for hereditary thrombophilia and antiphospholipid antibodies is suggested. Clinicians should be aware that coagulation function tests can be affected by anticoagulants. Consider also testing for hereditary thrombophilia in patients whose first-degree relative had DVT/PE. Good practice statement.
      Comment: There is no evidence on whether the results of thrombophilia or antiphospholipid antibodies testing impacts on any of the identified outcomes (rate of VTE recurrence, VTE related mortality, symptomatic/asymptomatic PE/DVT, psychological impact, patient preference or patient views) among patients who continue anticoagulant treatment [
      • Kozak P.M.
      • Xu M.
      • Farber-Eger E.
      • Gailani D.
      • Wells Q.S.
      • Beckman J.A.
      Discretionary thrombophilia test acquisition and outcomes in patients with venous thromboembolism in a real-world clinical setting.
      ], and avoiding thrombophilia testing is associated with preventable costs [
      • Bergstrom D.
      • Mital S.
      • Sheaves S.
      • Browne L.
      • O'Reilly D.
      • Nguyen H.V.
      Heritable thrombophilia test utilization and cost savings following guideline-based restrictions: an interrupted time series analysis.
      ]. Consequently, this recommendation relies only on experts’ consensus. Guideline committee focused on the higher basal likelihood of a positive test in people with an unprovoked VTE and the weight of additive information to inform the decision of continuing or stopping the treatment.

      4. Discussion

      In our EFIM document on management of patients with acute PE, we selected 35 recommendations focused on five clinical scenarios dealing with typical practice of aged, fragile and comorbid groups.
      A broad spectrum of complex clinical situations in patients with PE was covered related to diagnosis, and treatment of patients with cancer, pregnancy, CKD, anemia, thrombocytopenia or at risk of bleeding.
      Our document is dedicated to patients with complex clinical situations, as the feeling is that contemporary CPGs inconsistently report in these scenarios. Large registries show that the prevalence of comorbidities is not negligible in patients with acute PE [
      • Raskob G.E.
      • Angchaisuksiri P.
      • Blanco A.N.
      • Buller H.
      • Gallus A.
      • Hunt B.J.
      • et al.
      Thrombosis: a major contributor to global disease burden.
      ]. About 20 to 30% of these patients have cancer, many has reduced renal function, more than 40% are 70 years old or older [
      • Raskob G.E.
      • Angchaisuksiri P.
      • Blanco A.N.
      • Buller H.
      • Gallus A.
      • Hunt B.J.
      • et al.
      Thrombosis: a major contributor to global disease burden.
      ,
      • Barco S.
      • Mahmoudpour S.H.
      • Valerio L.
      • Klok F.A.
      • Münzel T.
      • Middeldorp S.
      • et al.
      Trends in mortality related to pulmonary embolism in the European Region, 2000-15: analysis of vital registration data from the WHO Mortality Database.
      ]. Also for these reasons prevalence of anemia and contraindications for CTPA are an everyday issue in the management of these patients.
      The recommendations were selected from 10 good-quality evidence-based and updated guidelines. With this adaptation process, we avoid wasting resources to develop new guidelines when guidance is already available, and we focus on facilitating practice in everyday care and on disseminating updated secondary evidence. Notably the recommendations that apply to our five clinical scenarios of patient with cancer, severe CKD, pregnancy, anemia or coagulation problems, gathered a high agreement and consistency across the original guideline sources. In many cases, the WG only needed to rewrite, and summarize the several original recommendations. Overall, the 35 recommendations are based on 3 high, 9 moderate, 4 low/moderate, 11 low, and 4 very low quality evidence, supported by 11 strong, 20 weak strength of the recommendation, and including also 4 good practice statements.
      To emphasize that 4 recommendations are based on “good practice” consensus, and there is no evidence on how to manage PE in anemic patients, neither when to evaluate underlines thrombosis cause in unprovoked PE. This apparently low evidence gap has been described for multimorbidity groups of patients [
      • Barnett K.
      • Mercer S.W.
      • Norbury M.
      • Watt G.
      • Wyke S.
      • Guthrie B.
      Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study.
      ,
      • Ruiz-Ruiz F.
      • Medrano F.J.
      • Navarro-Puerto M.A.
      • Rodríguez-Torres P.
      • Romero-Alonso A.
      • Santos-Lozano J.M.
      • et al.
      Delphi-RAND consensus of the Spanish Society of Internal Medicine on the controversies in anticoagulant therapy and prophylaxis in medical diseases. INTROMBIN Project (Uncertainty in thromboprophylaxis in internal medicine).
      ] that need to be filled by a wide-eyed internist research.
      In this guideline, the adaptation process was reproducible, following an explicit previously published method that strength their external validity [
      • Leśniak W.
      • Morbidoni L.
      • Dicker D.
      • Marín-León I.EFIM
      Clinical practice guidelines adaptation for internists - an EFIM methodology.
      ], as was the selection of well-founded primary guidelines and recommendations, when we got strong agreement between raters of the guidelines quality and within teams in search of the appropriate recommendations. When evidence is lacking some remarks are made to stimulate new research, as in anemic patients.
      Our guideline adaptation has some limitations. Firstly, this is a secondary summary of existing CPGs and the possible bias in the primary guidelines can be replicated, although possibly this is not an important issue when the high consistency across the original guidelines can be observed. Secondly, the trimmed scope of our guideline to a very few clinical situations in PE patient management is a limitation and make it impossible to develop clinical pathways. Thirdly, as the different original CPGs used different methodology to rate recommendation, we were forced to assemble a non-validated correspondence system to formulate the strength of the recommendation adapted to GRADE procedure, prioritizing the quality of evidence recorded in the GPCs. Fourthly, and last, there are some discordant recommendations from different CPGs which may result from different years of publication (and evidence available at that time), differences in the methodology which was used (using GRADE approach or other methods) and different values and preferences of the guideline panels from various countries in the world.
      These limitations do not downgrade the clinical relevance of this EFIM CPG that highlight recommendations, which are to be used by internists in difficult scenarios. Such recommendations are sometimes not to be found easily in subspecialty-specific guidelines.

      Acknowledgements

      We thank Mrs Anna Bagińska and Mrs Agata Zmyj from Polish Institute for Evidence Based Medicine for acquiring full texts of the guidelines, as well as prof. Remedios Otero Candelera (Seville, Spain) and prof. Stavros V Konstantinides (Mainz, Germany) for their efforts to external review the document.

      Appendix. Supplementary materials

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