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Pirogov Russian National Research Medical University (RNRMU), Department of Hospital Therapy named after academician P.E. Lukomsky, Moscow, Russian Federation
Instituto de Biomedicina de Sevilla (Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla), CIBERESP and Departmento de Medicina, Universidad de Sevilla, Seville, Spain
Department of Translational Medical Sciences, “Federico II” University Hospital and School of Medicine, Naples, ItalyCentre for Pulmonary Hypertension, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
Division of Internal Medicine, University Hospital of Basel, University of Basel, SwitzerlandShanghai University of Medicine and Health Sciences, Shanghai, China
Internal Medicine Department, Hospital Universitari Bellvitge - Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, SpainFaculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain
This EFIM guideline on pulmonary embolism adapts recommendations from existing CPGs. There were critical appraisal and adaptation of updated guidelines.
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It is useful to assist physicians in decision making of specific/complex scenarios.
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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.
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 [
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 [
Trends in mortality related to pulmonary embolism in the European Region, 2000-15: analysis of vital registration data from the WHO Mortality Database.
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 [
]. 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 [
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) [
]. 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 [
] 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 [
] (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.
Balshem et al. Journal of Clinical Epidemiology, 2011; 64: 401–406.
Quality level
Definition
High
We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate
We 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.
Low
Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low
We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
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 recommendations
is 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 patients
Most 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 clinicians
Most 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.
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?
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 [
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 [
] 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 [
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 [
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 [
Pulmonary embolism rule-out criteria (PERC) rule in European patients with low implicit clinical probability (PERCEPIC): a multicentre, prospective, observational study.
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 [
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 [
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
]. 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 [
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
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 [
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
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 [
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
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 [
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
]. 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 [
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 [
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 [
]. 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 [
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 [
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
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 [
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
] 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 [
]. 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 [
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 [
]. 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 [
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
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 [
], 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?
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
]. 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 [
] 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 [
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.
Poor predictive value of contemporary bleeding risk scores during long-term treatment of venous thromboembolism. A multicentre retrospective cohort study.
]: 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 [
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
]. 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 [
]. 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. 2Duration of anticoagulation (AC) after pulmonary embolism (PE) in patients who completed primary treatment. Comment: For additional information, see the text.
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
4.4. Discontinuation of therapeutic oral anticoagulation is recommended after 3 months if PE is provoked by transient (temporary, removable) risk factors [
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
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 [
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
]. 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 [
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
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 [
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
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 [
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
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 [
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 [
]. 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 [
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 [
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).
], 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.
Trends in mortality related to pulmonary embolism in the European Region, 2000-15: analysis of vital registration data from the WHO Mortality Database.
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).
Pulmonary embolism rule-out criteria (PERC) rule in European patients with low implicit clinical probability (PERCEPIC): a multicentre, prospective, observational study.
Effect of the pulmonary embolism rule-out criteria on subsequent thromboembolic events among low-risk emergency department patients: the PROPER Randomized Clinical Trial.
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.
Poor predictive value of contemporary bleeding risk scores during long-term treatment of venous thromboembolism. A multicentre retrospective cohort study.
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).
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