Diagnostiek VTE

Beoordeeld: 23-09-2025

Uitgangsvraag

Wat is de optimale diagnostiek van volwassen patiënten met een klinische verdenking van een Veneuze Trombo-Embolie (VTE)?

Aanbeveling

DVT

Voor volwassen patiënten met een verdenking op een eerste DVT

Pas een klinische beslisregel toe bij patiënten met een klinische verdenking van een DVT. Volg hierbij de stappen uit het stroomschema ‘Diagnostiek bij vermoeden op een (recidief) DVT’:

1. Hoge waarschijnlijkheid DVT op basis van klinische beslisregel

Voer compressie-echografie uit om de aanwezigheid van een proximale DVT aan te tonen dan wel uit te sluiten.

2. Lage waarschijnlijkheid DVT op basis van klinische beslisregel

Voer een D-dimeer test uit.

Indien D-dimeer test > 500 µg/L: Voer compressie-echografie uit om de aanwezigheid van een proximale DVT aan te tonen dan wel uit te sluiten.
Indien D-dimeer test ≤ 500 µg/L: proximale DVT is uitgesloten

Indien echografie laagdrempelig beschikbaar is: Overweeg om de combinatie klinische beslisregel/D-dimeer test over te slaan en direct een 2-punts compressie-echografie te verrichten om een proximale DVT uit te sluiten of aan te tonen.

Voor volwassen patiënten met een verdenking op een recidief DVT

Pas een klinische beslisregel toe bij patiënten met een klinische verdenking van een recidief DVT. Volg hierbij de stappen uit het stroomschema ‘Diagnostiek bij vermoeden op een (recidief) DVT’:

1. Hoge waarschijnlijkheid DVT op basis van klinische beslisregel

Voer compressie-echografie uit om de aanwezigheid van een proximale DVT aan te tonen dan wel uit te sluiten. Er is sprake van een recidief proximale DVT in het geval van een abnormale 2-punts compressie-echografie in een nieuw veneus segment of indien het niet comprimeerbare oude veneuze segment met ≥ 4 mm is toegenomen.

2. Lage waarschijnlijkheid DVT op basis van klinische beslisregel

Voer een D-dimeer test uit.

Indien D-dimeer test > 500 µg/L: Voer compressie-echografie uit om de aanwezigheid van een proximale DVT aan te tonen dan wel uit te sluiten. Er is sprake van een recidief proximale DVT in het geval van een abnormale 2-punts compressie-echografie in een nieuw veneus segment of indien het oude niet comprimeerbare veneuze segment met ≥ 4 mm is toegenomen.
Indien D-dimeer test ≤ 500 µg/L: proximale DVT uitgesloten

Indien de compressie echografie niet eenduidig is: overweeg om een MRDTI toe te passen teneinde een recidief DVT aan te tonen dan wel uit te sluiten.

Longembolie

Sluit een eerste of herhaalde episode van longembolie uit met behulp van een lage klinische voorafkans (vastgesteld met een beslisregel) en een normale D-dimeer test bij patiënten met een verdenking op een longembolie. Overweeg hierbij om het YEARS-algoritme te gebruiken.

Sluit een eerste of herhaalde episode van een longembolie uit of toon een longembolie aan met een CTPA bij patiënten met een hoge klinische waarschijnlijkheid of afwijkende D-dimeer test.

Volg hierbij de stappen uit het stroomschema ‘Diagnostiek bij verdenking op een longembolie’.

Overwegingen

Voor- en nadelen van de interventie en de kwaliteit van het bewijs

DVT

Bij patiënten met een klinische verdenking op DVT hebben klinische beslisregels – waarvan de Wells-regel de meest gebruikte is (Wells, 2003) – in combinatie met een D-dimeer test mogelijk een hoge negatief voorspellende waarde (NPV) en hoge sensitiviteit om een proximale DVT uit te sluiten, maar een lage specificiteit om de diagnose DVT vast te stellen. De bewijskracht hiervoor is laag door de verschillende prevalenties (12% in Parpia (2019) en 26% in Geersing (2014)), toegepaste referentiestandaarden en indextesten (mix kwalitatieve en kwantitatieve D-dimeer assay) in de studies. Voor de NPV kon per diagnostische strategie alleen een puntschatting worden berekend, waardoor informatie over de spreiding en heterogeniteit niet te bepalen was.

De hoge sensitiviteit en NPV betekent dat patiënten met een negatieve uitslag geen diagnostisch vervolgonderzoek (echografie) hoeven te ondergaan. De lagere specificiteit betekent dat fout positieven kunnen optreden als alleen klinische beslisregels in combinatie met een D-dimeer test wordt gehanteerd om een DVT aan te tonen, dus dat vervolgonderzoek vereist is om een diagnose te stellen.

Twee-punts compressie-echografie heeft een hoge sensitiviteit (90,1% (95% BI: 86,5 tot 92,8) om een eerste episode van proximale DVT uit te sluiten en een hoge specificiteit 98,5% (95% BI 97,6 tot 99,1%) om een eerste episode van proximale DVT aan te tonen (Lensing, 1989 en Bhatt, 2020). Dit is dus het beeldvormend vervolgonderzoek van keuze om DVT aan te tonen of uit te sluiten. Omdat 2-punts compressie-echografie veelal laagdrempelig beschikbaar is, steeds meer met point-of-care echomachines uitgevoerd wordt, goedkoop is en geen nadelige effecten op de patiënt heeft, kan ervoor gekozen worden om de stap met de voorafkans bepaling en D-dimeer test over te slaan. Als alternatief kan een zogenaamde complete compressie-echografie worden uitgevoerd. Deze methode is arbeidsintensiever omdat meer veneuze segmenten in het bovenbeen en onderbeen onderzocht moeten worden. Daarnaast is het potentiële probleem van overdiagnostiek van geïsoleerde kuit(spier)vene tromboses waarvan de noodzaak voor behandeling wordt betwijfeld (Bernardi, 2008). De NHG-Standaard kiest daarom voor een 2-punts compressie-echografie (CUS). Indien men kiest om een complete CUS uit te voeren en deze niet beschikbaar is buiten kantooruren kan alsnog een 2-punts compressie-echografie worden uitgevoerd volgens het stroomschema.

Bij klinische verdenking op een recidief DVT is de echografie minder specifiek door het frequent voorkomen van persisterende stolselresten na een eerste DVT. Zo bleek in een retrospectieve studie, dat bij 29 van de 90 patiënten (32%) bij wie een CUS was verricht vanwege een verdenking van een recidief ipsilaterale DVT, de diagnose niet met zekerheid kon worden gesteld door ontbreken van eerder aanwezige CUS-uitslagen, met als gevolg dat deze patiënten mogelijk onterecht met langdurige antistolling behandeld werden. (Tan, 2010). De persisterende stolselresten kunnen vaak niet goed onderscheiden worden van een nieuwe DVT-episode, tenzij er een uitgangsechografie aanwezig is die aantoont dat een stolsel is ontstaan in een nieuw veneus segment, of dat de comprimeerbaarheid van het vat met tenminste 2-4 mm is afgenomen. Het maken van een uitgangscompressie-echografie in alle patiënten die stoppen met antistolling na een eerste DVT in de Nederlandse situatie is echter niet kosteneffectief gebleken (de Jong, 2023). Uit onderzoek blijkt dat ‘MR direct thrombus imaging’ (MRDTI) een vers stolsel kan onderscheiden van stromend bloed of een chronisch reststolsel, door de metabole omzetting van hemoglobine in methemoglobine (Tan, 2014 en van Dam, 2020). Indien compressie echografie geen zekerheid geeft, kan MRDTI worden toegepast om een finale diagnose te stellen. In de Nederlandse situatie is aangetoond dat het gebruik van deze techniek kosteneffectief is (van Dam, 2021). De MRDTI kan vanaf een half jaar na de index DVT-diagnose gebruikt worden (voor die tijd kan de MRDTI nog positief zijn), en wordt het best ingezet in de eerste dagen tot twee weken het na ontstaan van de symptomen (van Dam, 2020).

Longembolie

Bij patiënten met een klinische verdenking op een longembolie, met klachten die minder dan twee weken geleden zijn ontstaan, hebben klinische beslisregels in combinatie met een D-dimeer test mogelijk een hoge negatief voorspellende waarde en hoge sensitiviteit voor het uitsluiten, maar een lage specificiteit om de diagnose longembolie vast te stellen. Het YEARS-algoritme is een veilig, efficiënt en kosteneffectief diagnostisch algoritme (Van der Pol, 2018). Het merendeel (86%) van de patiënten presenteerde zich op de spoedeisende hulp. In subgroep analyses is de NPV lager in patiënten met kanker of een verleden van eerder doorgemaakte VTE. De bewijskracht hiervoor is laag door verschillen in prevalentie, de referentiestandaard en gebruikte indextest in de studies. Voor de NPV kon per diagnostische strategie alleen een puntschatting worden berekend, waardoor informatie over de spreiding en heterogeniteit niet te bepalen was. Het YEARS-algoritme is eenvoudig te gebruiken in de dagelijkse praktijk en wordt in Nederlandse ziekenhuizen veel toegepast. Ook worden juist in jongere patiënten CT-scans voorkomen, in tegenstelling tot de leeftijdsafhankelijke D-dimeer afkapwaarde. Om deze redenen verdient dit algoritme de voorkeur.

De hoge sensitiviteit en NPV betekent dat patiënten met een negatieve uitslag geen diagnostisch vervolgonderzoek (CT-scan) hoeven te ondergaan. De lagere specificiteit betekent dat fout positieven kunnen optreden als alleen klinische beslisregels in combinatie met een D-dimeer test wordt gehanteerd om een longembolie vast te stellen, dus dat vervolgonderzoek vereist is om een diagnose te stellen. De interpretatie van de hogere incidentie van fout-negatieve uitslagen bij patiënten met een voorgeschiedenis van VTE en kanker is complex. Allereerst is de achtergrond incidentie van (nieuwe) VTE in deze patiëntengroep duidelijk hoger dan in personen zonder deze voorgeschiedenis. Dat blijkt ook uit de observatie dat de incidentie van een fout-negatieve CT-uitslag ook hoger is bij deze patiënten (Stals, 2022 en van der Pol, 2018). Voor de berekening van de proportie van fout-negatieve uitslagen wordt gekeken in een periode van drie maanden, waarbij het de vraag is of een nieuwe VTE na twee maanden follow-up daadwerkelijk een gemiste diagnose is, of een nieuwe episode. De hoogste proportie van fout-negatieve uitslagen wordt gevonden in de meer recent ontworpen diagnostische algoritmes zoals YEARS. Dat wordt mogelijk voor een deel verklaard door een werkelijk hoger aantal gemiste diagnoses omdat het aantal CT-scans dat wordt gemaakt veel lager ligt, maar ook omdat een deel van de gemiste diagnoses kleine, subsegmentele longembolieën betreffen, waarvan de relevantie onduidelijk is (van der Pol, 2018). Het is dus de vraag of dit geen overdiagnostiek betreft, en het werkelijk relevante diagnostische missers zijn. In studies, waarin de nieuwe algoritmes daadwerkelijk zijn toegepast, was er geen belangrijk signaal van een opvallend hoog aantal gemiste diagnoses als op basis van YEARS de diagnose zonder beeldvorming was uitgesloten. Een laatste argument is dat, vooral in de groep patiënten met een actieve maligniteit, onverwacht overlijden tijdens de studie frequent voorkwam en in de regel op conservatieve wijze geduid werd als recidief longembolie (Stals, 2022). In algoritmes waar een lagere proportie van patiënten aan een CT-scan wordt onderworpen, neemt het aantal overlijdens -en dus vaak meegetelde diagnostische missers- proportioneel toe in de groep die geen CT-scan kreeg.

CT-pulmonalis angiografie (CTPA) heeft een hoge sensitiviteit (83-100%) om zowel een eerste als herhaalde episode van longembolie uit te sluiten en een hoge specificiteit (89-97-%) om zowel een eerste als herhaalde episode van longembolie aan te tonen (Remy-Jardin, 2007). Deze scan is in alle Nederlandse ziekenhuizen laagdrempelig beschikbaar en geldt als eerste keus beeldvormende test bij verdenking longembolie. Het voordeel van CTPA boven nucleair onderzoek (ventilatie-perfusie scan) is het lagere aantal niet-diagnostische uitslagen, de betere mogelijkheid om met deze beeldvorming gelijktijdig een alternatieve diagnose te stellen en de informatie over hartfunctie – rechter-linker ventrikel ratio - die geëxtraheerd kan worden en prognostische relevantie heeft voor patiënten met een aangetoonde longembolie. Het nadeel van CTPA ten opzichte van nucleair onderzoek is dat er meer ioniserende stralen aan te pas komen, wat voornamelijk bij jongere personen en vrouwen een zorg is. Daarnaast kunnen soms ernstige allergische reacties optreden bij toediening van het contrast. Vanwege deze - en logistieke redenen is het beperken van het aantal CTPA-scans een prioriteit. In de afweging over welke diagnostische strategie preferentieel gebruikt wordt, is de efficiëntie van het algoritme dan ook relevant.

In de IPDMA van patiënten met verdenking longembolie zoals in deze module besproken, waren geen zwangere vrouwen geïncludeerd. Een alternatieve diagnostische regel (LEFt) voor zwangere patiënten met een klinische verdenking van DVT wordt momenteel prospectief gevalideerd, maar is dus formeel niet inzetbaar in de dagelijkse praktijk. Bij zwangeren met een hoge verdenking op een DVT maar een normale echo moet gedacht worden aan een geïsoleerde bekkenvene trombose. Aanwijzingen daarvoor kunnen gevonden worden met doppler echografie. Ook de MRDTI-scan is uitermate geschikt voor het stellen van deze diagnose omdat er geen contrast voor nodig is en niet gepaard gaat met ioniserende straling.

Voor zwangere patiënten met verdenking longembolie geldt dat de diagnostische algoritmen van de niet zwangere patiënten gevolgd kunnen worden (van der Pol, 2019). Voor kinderen gelden andere algoritmen (buiten het bestek van deze module). Bij patiënten met kanker is de kans op een nieuwe diagnose DVT of longembolie na het uitsluiten van een longembolie (zowel middels beslisregel/D-dimeer test als CT-scan) twee tot vier keer hoger dan bij patiënten zonder kanker. Er loopt onderzoek om vast te stellen wat de meerwaarde is van het volgen van het YEARS-algoritme boven direct en alleen een CT-scan in alle patiënten. Patiënten met kanker zijn meegenomen in de studies waarin de diagnostische algoritmes met een beslisregel en D-dimeer test zijn getest. Om die reden en tot deze studie afgerond is, kan de diagnostiek bij hen ook volgens het routine algoritme verlopen.

Patiënten die therapeutische antistolling gebruiken op het moment van verdenking op VTE dienen meteen verwezen te worden voor een beeldvormende test: de D-dimeer test kan door de antistolling een lage waarde geven, waarmee de sensitiviteit en daarmee de NPV ruimschoots buiten de gestelde veiligheidsnorm vallen.

Waarden en voorkeuren van patiënten (en evt. hun verzorgers)

Het belangrijkste doel van het diagnostische traject bij een vermoeden op een VTE is het op veilige wijze uitsluiten dan wel aantonen van een diepe veneuze trombose of een longembolie. Het belangrijkste voordeel van het diagnostisch algoritme is dat in een groot deel van de patiënten geen radiologisch onderzoek nodig is. Bij de diagnostiek van longembolie betekent dit dat er geen CT-scan nodig is (wat gepaard gaat met stralenbelasting), dat de doorlooptijd op de spoedeisende hulp korter is en dat de patiënt sneller duidelijkheid heeft over de diagnose.

Kosten (middelenbeslag)

Er is aangetoond dat het invoeren van het YEARS-algoritme ten opzichte van het gebruik van de Wells-regel en een D-dimeer test met een vaste afkapwaarde resulteert in een kostenbesparing op de Spoedeisende hulp (van der Pol, 2018). Een formele kosteneffectiviteitsanalyse ontbreekt in de literatuur.

Aanvaardbaarheid, haalbaarheid en implementatie

Er is geen kwantitatief of kwalitatief onderzoek gedaan naar de aanvaardbaarheid en haalbaarheid van de diagnostische procedures. Met betrekking tot diagnostische procedures wordt er in de praktijk altijd een afweging gemaakt tussen veiligheid (het al dan niet missen van een aandoening) en efficiëntie (geen onnodige diagnostische procedures).

De aanbevolen diagnostische algoritmen die besproken worden in deze richtlijn, worden momenteel gebruikt door het grootste deel van de Nederlandse ziekenhuizen. Veel van de studies zijn uitgevoerd in de Nederlandse setting, wat de validiteit van de resultaten voor de Nederlandse setting onderstreept. De werkgroep verwacht daarom geen problemen ten aanzien van de haalbaarheid, aanvaardbaarheid en implementatie.

DVT

Rationale van de aanbeveling: weging van argumenten voor en tegen de diagnostische procedure

De combinatie van een klinische beslisregel en een D-dimeer test is een eenvoudige, veilige en non-invasieve manier om een proximale DVT uit te sluiten. Het voordeel hiervan is dat deze combinatie van testen aan het bed van de patiënt kan worden uitgevoerd en er geen noodzaak is om beeldvorming te verrichten. Voor het aantonen en het uitsluiten van een DVT bij een patiënt met een hoge klinische waarschijnlijkheid op de aandoening is een compressie-echografie noodzakelijk. Compressie-echografie neemt weinig tijd in beslag en is laagdrempelig beschikbaar.

Longembolie

Rationale van de aanbeveling: weging van argumenten voor en tegen de diagnostische procedure

De combinatie van een klinische beslisregel en een D-dimeer test is een eenvoudige, veilige en non-invasieve manier om een longembolie uit te sluiten indien de klinische waarschijnlijkheid op deze aandoening niet hoog is. Het voordeel hiervan is dat deze combinatie van testen aan het bed van de patiënt kan worden uitgevoerd en er geen noodzaak is om een imaging test uit te voeren. Voor het aantonen en uitsluiten van een longembolie bij een patiënt met een hoge klinische waarschijnlijkheid op de aandoening is een CTPA noodzakelijk. CTPA is laagdrempelig beschikbaar en is de meest gebruikte radiologische modaliteit. De werkgroep adviseert om te overwegen hierbij het YEARS-algoritme te gebruiken. Ondanks een lagere NPV in de subgroepen van patiënten met kanker en patiënten met een VTE in de voorgeschiedenis, is er naar de mening van de werkgroep onvoldoende aanleiding om het YEARS-algoritme niet aan te bevelen in deze groepen.

Onderbouwing

Achtergrond

It has become routine to start the diagnostic process in patients suspected of deep vein thrombosis (DVT) or pulmonary embolism (PE) with a clinical decision rule and a D-dimer test. Based on the results of these two tests, selective imaging is applied to exclude or confirm a diagnosis. This means that patients with a negative result of the clinical decision rule and D-dimer test do not need expensive and time-consuming diagnostic follow-up examination (i.e. radiological imaging). It is important to determine the accuracy of the clinical decision rules in combination with D-dimer testing. It is important that a negative test result really excludes the diagnosis, so has a high negative predictive value (NPV).

Conclusies / Summary of Findings

Part I: Deep vein thrombosis (DVT)

Negative predictive value

Low

GRADE

The evidence suggests that clinical decision rules plus d-dimer testing may have a high negative predictive value in patients suspected of having deep vein thrombosis in the referred secondary care setting.

Sources: Geersing, 2014; Parpia, 2019

Specificity and sensitivity

Low

GRADE

The evidence suggests that clinical decision rules plus d-dimer testing may be sensitive but not specific in diagnosing patients suspected of having deep vein thrombosis.

Source: Parpia, 2019

Part II: Pulmonary embolism (PE)

Negative predictive value

Overall

Low

GRADE

The evidence suggests that clinical decision rules plus d-dimer testing may have a high negative predictive value in patients suspected of having pulmonary embolism in the referred secondary care setting.

Source: Geersing 2022

Subgroups

Low

GRADE

In patients with cancer or a history of VTE, the evidence suggests that clinical decision rules plus d-dimer testing may have a lower negative predictive value for patients suspected of having pulmonary embolism in the hospital setting than the patients without cancer and/or a history of VTE.

Source: Stals 2022

Specificity and sensitivity

Moderate

GRADE

The evidence suggests that clinical decision rules plus d-dimer testing likely are sensitive but not specific in diagnosing patients suspected of having pulmonary embolism in the referred secondary care setting.

Source: Geersing 2022

Samenvatting literatuur

Description of studies

Part I: Deep vein thrombosis (DVT)

Geersing (2014) performed an IPD meta-analysis to assess the safety of an unlikely score on the Wells rule combined with a negative D-dimer test result for excluding DVT in outpatients. The authors report the diagnostic failure rate and efficiency for different settings, including in the secondary/hospital setting. Studies were included if they (1) included outpatients with clinically suspected DVT, (2) assessed variables to calculate the Wells rule, (3) had a prospective follow-up design, and (4) applied a reference standard of imaging and/or clinical follow-up for three months in those in whom DVT was ruled out without imaging. A previous meta-analysis and literature search to update the results from 2006 yielded 13 studies that fulfilled these criteria, resulting in a sample size of 10,002 patients. A DVT diagnosis was present in 1864 (19%) of all patients; the prevalence varied from 5% to 39% between studies. 62% were female and the median age was 59 years. The subgroup analysis for hospital care for studies with D-dimer data included 4,511 patients from 5 studies with a prevalence varying from 16% to 39%. For D-dimer testing both qualitative and quantitative assays were used, with a mix of thresholds for the quantitative assays (the threshold used within the study). The IPD meta-analysis was performed on imputed data with multilevel logistic regression models involving a random intercept for study (to account for the clustering of patients within studies). Two outcome measures were reported by the authors: (1) diagnostic failure rate: the mean predicted probability of DVT in patients with a score ≤1 on the Wells rule combined with a negative D-dimer test result and (2) efficiency: the proportion of individuals classified by the strategy as DVT considered excluded without imaging. Thus, the failure rate is similar to a false negative test result (i.e. 1 minus negative predictive value) and efficiency is similar to the true negatives plus false negatives as proportion of the total study population.

Parpia (2019) performed an IPD meta-analysis to assess the accuracy of different clinical decision rules (CDRs) for excluding DVT in outpatients. The CDRs investigated were Wells score ≤ 1 combined with either a fixed (500 μg/L) or age-adjusted D-dimer thresholds (age x 10 μg/L in patients aged >50 years). This study used three studies that quantitatively measured D-dimer levels from the IPD database established by Geersing (2014) plus one additional study performed by their group. Studies were included if they (1) included outpatients with clinically suspected DVT, (2) assessed variables to calculate Wells rule, (3) had a prospective follow-up design, (4) applied a reference standard of imaging and/or clinical follow-up for three months in those in whom DVT was ruled out without imaging at initial presentation and (5) used quantitative D-dimer assays. Four studies with 3,368 patients fulfilled these criteria. 814 patients with a Wells score of >2 were excluded as D-dimer is not recommended to exclude DVT in these patients. Ultimately, 2554 patients were included in the analysis. A DVT diagnosis was present in 12% of all patients; this prevalence varied from 5% to 31% between studies. Distribution of patients in Wells 0 or 1-2 also varied across studies. 64% of all patients were female, the mean age was 59 years and 44% had a low CPTP. Three studies were performed in the secondary care setting and one study in the primary care setting. The authors performed a two-stage meta-analysis, first obtaining summary estimates for each separate study, and second combining these using a meta-analysis model.

Part II: Pulmonary embolism(PE)

Geersing (2022) performed a systematic review and IPD meta-analysis to examine the use of different CDRs for ruling out acute PE in a variety of healthcare settings. The CDRs investigated were Wells and revised Geneva scores combined with D-dimer interpretations either using a fixed cut-off (using either qualitative or quantitative D-dimer testing), adjusted to pretest probability (PTP), or age-adjusted D-dimer thresholds (age x 10 μg/L in patients aged >50 years), as well as the YEARS algorithm. In the YEARS algorithm the D-dimer threshold depends on clinical pretest probability (CPTP) assessment (as in: higher D-dimer threshold for patients with a low CPTP). For the PTP adjusted D-dimer levels, low probability (Wells score of ≤4 or Geneva score of ≤5) has a D-dimer cut-off of 1000 ng/ml and moderate probability (Wells score of > 4 or Geneva score of ≥6) has a D-dimer cut-off of 500 ng/ml. If PE could not be ruled out based on the combination of CDR and D-dimer testing, a computed tomography pulmonary angiography (CTPA) was ordered to confirm or refute the diagnosis. Studies were included if they (1) included patients with clinically suspected PE, (2) assessed variables to calculate at least 1 of the CDRs of interest, (3) had a prospective follow-up or cross-sectional study design, (4) provided a clear description of the healthcare setting, (5) involved at least 50 patients with confirmed VTE and (6) applied a reference standard of either imaging or a clinical follow-up of at least 1 month in those in whom PE was ruled out at initial presentation without imaging. In addition, studies were excluded if only qualitative D-dimer measurements were performed and patients with only low clinical pretest probability were included. A literature search from 1 January 1995 until 1 November 2021 in MEDLINE yielded 23 studies that fulfilled these criteria, accumulating to 35,248 patients available for analysis. For referred secondary care, the analysis included 14 studies with 17,052 patients and a mean baseline PE prevalence of 20%. This prevalence varied from 14% to 41% between studies. Four outcome measures were reported by the authors: (1) diagnostic failure rate: “the predicted 3-month VTE incidence after exclusion of PE without imaging at baseline”; (2) efficiency: “the proportion of individuals classified by the strategy as PE considered excluded without imaging tests”; (3) sensitivity and (4) specificity. The IPD meta-analysis was performed on imputed data with multilevel logistic regression models involving a random intercept for study (to account for the clustering of patients within studies) for failure rate and efficiency. For sensitivity and specificity, univariate random effects modeling was used due to nonconvergence issues encountered in bivariate random effects modeling.

Stals (2022) performed a systematic review and IPD meta-analysis using the same dataset as the Geersing study described above, to examine the use of different CDRs for ruling out acute PE in important patient subgroups. The CDRs investigated were Wells and revised Geneva scores combined with fixed (500 μg/L) and age-adjusted D-dimer thresholds (age x 10 μg/L in patients aged >50 years), as well as the YEARS algorithm. In the YEARS algorithm the D-dimer threshold depends on clinical pretest probability (CPTP) assessment (as in: higher D-dimer threshold for patients with a low CPTP). If PE could not be ruled out based on the combination of CDR and D-dimer testing, a computed tomography pulmonary angiography (CTPA) was ordered to confirm or refute the diagnosis. Studies were included if they (1) included patients with clinically suspected PE, (2) assessed variables to calculate at least 1 of the CDRs of interest, (3) had a prospective follow-up or cross-sectional study design and (4) applied a reference standard of either imaging or clinical follow-up in those in whom PE was ruled out without imaging. In addition, studies were excluded if only qualitative D-dimer measurements were performed and patients with only low clinical pretest probability were included. A literature search from 1 January 1995 until 1 January 2021 in MEDLINE yielded 16 studies that fulfilled these criteria, accumulating to 20 553 patients available for analysis. A VTE diagnosis was present in 3932 (19%) of all patients; this prevalence varied from 7.4% to 41% between studies. The IPD meta-analysis was performed on imputed data with multilevel logistic regression models with a random intercept for study (to account for the clustering of patients within studies). Two outcome measures were reported by the authors: (1) diagnostic failure rate: “the predicted 3-month VTE incidence after exclusion of PE without imaging at baseline.” and (2) efficiency: “the proportion of individuals classified by the strategy as PE considered excluded without imaging tests”. The authors performed pre-defined subgroup analyses for active cancer (as defined in the original studies) and history of VTE.

Results

Part I: Deep vein thrombosis (DVT)

Negative predictive value

In the study of Geersing (2014), 4,511 patients were analysed in an IPD meta-analysis to assess the accuracy of an unlikely score on the Wells rule (≤1) combined with a negative D-dimer test result for excluding DVT.

Enough information was available to post hoc estimate the negative predictive value (NPV) as following: NPV = 1 – failure rate. Results are shown in Table 1.

In the study of Parpia (2019), 2,554 patients with low (≤0) or moderate (1-2) Wells scores were analysed in an IPD meta-analysis to assess the accuracy of different CDRs for excluding DVT in hospital and primary care outpatients. Restricting to a population with low or moderate Wells-pre-test probability means a lower prevalence of DVT, which can lead to higher NPV estimates. Results are shown in Table 1.

Sensitivity and specificity

Table 1. Failure rate, efficiency, negative predictive value (NPV), sensitivity and specificity for an unlikely score on the Wells rule combined with a negative D-dimer test result for ruling out DVT (Geersing, 2014 and Parpia, 2019)

Study	Clinical decision rule	N	Prevalence DVT	Failure rate (% (95%CI))	Efficiency (% (95%CI))	NPV (% (95%CI))	Sensitivity (% (95%CI))	Specificity (% (95%CI))
Geersing (2014)	Wells score (≤1) and negative D-dimer test	4511	26%	0.9 (0.0 to 1.9)	23.1% (12.8 to 38.3)	99.1**	-	-
Parpia (2019)*	Wells score (≤0) and D-dimer <500 μg/L	2554	12%	0.2**	38.9 (29.1 to 48.7)	99.8 (99.5 to 100)	99.0 (97.8 to 100.0)	45.2 (39.6 to 50.9)
Parpia (2019)*	Wells score (≤0) and age- adjusted D-dimer (age x 10 μg/L for >50 years)	2554	12%	0.3**	47.4 (35.3 to 59.3)	99.7 (99.4 to 100.0)	98.0 (96.3 to 99.5)	54.7 (48.3 to 61.2)

^{* Parpia (2019) only included patients with low or moderate clinical pre-test probability on the Wells score. The lower prevalence of DVT can lead to higher NPV estimates.}

^{** Enough information was available to post hoc estimate the negative predictive value (NPV) or failure rate as following: NPV = 1 - failure rate}

Part II: Pulmonary embolism (PE)

Negative predictive value overall

In the study of Geersing (2022), 17,052 patients were analysed in an individual patient data meta-analysis to examine the use of different CDRs for ruling out acute PE in referred secondary care. Enough information was available to post hoc estimate the negative predictive value (NPV) for different CDRs as following: NPV = 1 - failure rate. Results are shown in Table 2. Using the Wells score with PTP adjusted D-dimer resulted in a NPV of 96.9, which is just below the minimally clinically relevant threshold of 97%.

Table 2. Failure rate, efficiency, negative predictive value (NPV), sensitivity and specificity for different clinical decision rules for ruling out acute PE (Geersing, 2022)

Clinical decision rule	N	Failure rate (% (95%CI))	Efficiency (% (95%CI))	NPV (%)*	Sensitivity (% (95%CI))	Specificity (% (95%CI))
Wells score with qualitative/fixed D-dimer threshold <500 μg/L	15 531	0.75 (0.50 to 1.13)	29.57 (25.39 to 34.12)	99.3	98.38 (95.87 to 99.41)	36.89 (32.53 to 41.47)
Wells score with fixed D-dimer threshold <500 μg/L	15 114	0.32 (0.17 to 0.60)	27.77 (23.05 to 33.03)	99.7	99.59 (99.10 to 99.82)	35.21 (30.19 to 40.57)
Wells score with age-adjusted D-dimer threshold (age x 10 μg/L for >50 years)	15 114	0.65 (0.43 to 0.99)	32.91 (27.85 to 38.39)	99.4	98.93 (98.15 to 99.39)	41.58 (36.42 to 46.93)
Wells score with PTP adjusted D-dimer	15 114	3.06 (2.47 to 3.78)	48.78 (43.64 to 53.94)	96.9	93.25 (91.91 to 94.38)	60.80 (56.24 to 65.19)
Revised Geneva score with qualitative/fixed D-dimer threshold <500 μg/L	13 245	1.17 (0.79 to 1.74)	30.46 (26.75 to 34.44)	98.8	97.75 (93.86 to 99.27)	39.25 (34.57 to 44.14)
Revised Geneva score with fixed D-dimer threshold <500 μg/L	12 828	0.37 (0.19 to 0.74)	28.77 (26.20 to 31.48)	99.6	99.53 (98.88 to 99.80)	37.23 (34.00 to 40.57)
Revised Geneva score with age-adjusted D-dimer threshold (age x 10 μg/L for >50 years)	12 828	0.81 (0.51 to 1.27)	35.25 (32.76 to 37.82)	99.2	98.51 (97.37 to 99.16)	45.27 (42.63 to 47.95)
Revised Geneva score with PTP adjusted D-dimer	12 828	2.95 (2.34 to 3.71)	43.02 (38.28 to 47.31)	97.1	98.51 (97.37 to 99.16)	45.27 (42.63 to 47.95)
YEARS algorithm (D-dimer threshold, 1000 μg/L if 0 YEARS items and D-dimer 500 μg/L if 1–3 YEARS items)	15 114	2.10 (1.59 to 2.75)	43.38 (38.86 to 48.01)	97.9	96.15 (94.87 to 97.12)	54.39 (49.87 to 58.85)

^{* Enough information was available to post hoc estimate the negative predictive value (NPV) for different CDRs as following: NPV = 1 - failure rate}

Negative predictive value in two subgroup analyses

Two subgroups were analysed: patients with cancer and history of VTE. These subgroups were arbitrarily chosen because their patient characteristics may influence the performance of the diagnostic algorithms. In particular, the prevalence of VTE is often higher, and as a result the NPV is lower. As a result, certain algorithms may be less safe. In the study of Stals (2022), 20,553 patients were analysed in an individual patient data meta-analysis to examine the use of different CDRs for ruling out acute PE. Sufficient information was available to post-hoc estimate the negative predictive value (NPV) for different CDRs as follows: NPV = 1 - failure rate. Results for the subgroup analyses for active cancer are shown in Table 3. Results for the subgroup analyses for history of VTE are shown in Table 4. In cancer patients and patients with a history of VTE, the NPV is slightly below the minimally clinically relevant threshold of 97%, when using the YEARS algorithm. However, as the baseline prevalence of PE is considerably higher in those specific subgroups and the sensitivity was above 90% (data not reported in Stals (2022) but retrieved by personal communication), these NPV’s (96.6 and 96.5, respectively) are within the acceptable range (Dronkers, 2021).

Table 3. Failure rate, efficiency, and negative predictive value (NPV) for different clinical decision rules for ruling out acute PE in patients with and without cancer (Stals, 2022)

Clinical decision rule	No cancer (N = 18,334)			Cancer (N = 2,219)
	Failure rate (% (95%CI))	Efficiency (% (95%CI))	NPV*	Failure rate (% (95%CI))	Efficiency (% (95%CI))	NPV*
Wells score with fixed D-dimer threshold (500 μg/L)	0.36 (0.14–0.94)	28 (12–53)	99.6	No failures	9.6 (3.4–24)	100
Wells score with age-adjusted D-dimer threshold (age x 10 μg/L for >50 years)	0.74 (0.32–1.7)	34 (17–56)	99.3	1.1 (0.25–4.7)	15 (6.2–31)	98.9
Revised Geneva score with fixed D-dimer threshold (500 μg/L)	0.5(0.21–1.4)	33 (15–57)	99.4	1.3 (0.26–6.6)	12 (4.6–27)	98.7
Revised Geneva score with age-adjusted D-dimer threshold (age x 10 μg/L for >50 years)	1 (0.43–2.5)	39 (22–60)	99	2.5 (0.73–8.0)	18 (8.5–34)	97.5
YEARS algorithm (D-dimer threshold, 1000 μg/L if 0 YEARS items and D-dimer 500 μg/L if 1–3 YEARS items)	1.7 (0.74–4.0)	44 (24–66)	98.3	3.4 (1.2–9.0)	21 (9.6–39)	96.6

^{* Enough information was available to post hoc estimate the negative predictive value (NPV) for different CDRs as following: NPV = 1 -failure rate}

Table 4. Failure rate, efficiency, and negative predictive value (NPV) for different clinical decision rules for ruling out acute PE in patients with and without a history of VTE (Stals, 2022)

Clinical decision rule	No history of VTE (N = 17611)			History of VTE (N = 2942)
	Failure rate (% (95%CI))	Efficiency (% (95%CI))	NPV*	Failure rate (% (95%CI))	Efficiency (% (95%CI))	NPV*
Wells score with fixed D-dimer threshold (500 μg/L)	0.33 (0.14–0.77)	30 (13–55)	99.7	0.48 (0.07–3.4)	12 (4.5–28)	99.5
Wells score with age-adjusted D-dimer threshold (age x 10 μg/L for >50 years)	0.70 (0.35–1.4)	36 (19–57)	99.3	1.0 (0.23–4.3)	15 (6.7–30)	99
Revised Geneva score with fixed D-dimer threshold (500 μg/L)	0.48 (0.21–1.1)	33 (15–58)	99.5	1.2 (0.39–3.3)	21 (8.6–43)	98.8
Revised Geneva score with age-adjusted D-dimer threshold (age x 10 μg/L for >50 years)	0.87 (0.43–1.7)	39 (21–60)	99.1	2.5 (1.1–5.7)	27 (14–47)	97.5
YEARS algorithm (D-dimer threshold, 1000 μg/L if 0 YEARS items and D-dimer 500 μg/L if 1–3 YEARS items)	1.5 (0.77–2.9)	44 (24–66)	98.5	3.5 (1.7–7.2)	32 (16–54)	96.5

^{* Enough information was available to post hoc estimate the negative predictive value (NPV) for different CDRs as follows: NPV = 1 - failure rate}

Sensitivity and specificity

Level of evidence of the literature

Part I: Deep vein thrombosis (DVT)

The evidence was derived from one systematic review with an IPD meta-analysis and a second follow-up IPD meta-analysis. The level of evidence for all reported outcome measures started at ‘high quality’.

Negative predictive value

The level of evidence regarding the critical outcome measure negative predictive value was downgraded by two levels to low, because of: study limitations including differences in the index test (mix qualitative and quantitative D-dimer assays with different thresholds), heterogeneity in DVT prevalence, lack of blinding of the reference standard assessor, only point estimates for NPV could be post hoc estimated from the reported information, and exclusion of patients with a Wells score >2 in the study of Parpia et al (2019) (-2 risk of bias).

Sensitivity and specificity

The level of evidence regarding the important outcome measure sensitivity was downgraded by two levels to low because of: study limitations including different settings (one of four studies included in meta-analysis in the primary care setting), heterogeneity in DVT prevalence and distribution of patients in Wells 0 or 1-2, lack of blinding of the reference standard assessor, and exclusion of patients with a Wells score >2 (-2 risk of bias).

The level of evidence regarding the important outcome measure specificity was downgraded by two levels to low because of: study limitations including different settings (primary and secondary care), heterogeneity in DVT prevalence and distribution of patients in Wells 0 or 1-2, lack of blinding of the reference standard assessor, and exclusion of patients with a Wells score >2 (-2 risk of bias).

Part II: Pulmonary embolism

The evidence was derived from two systematic reviews and IPD meta-analyses. The level of evidence for all reported outcome measures started at ‘high quality’.

Negative predictive value overall

For the main results, the level of evidence regarding the critical outcome measure negative predictive value was downgraded by two levels to low because of: study limitations including heterogeneity in prevalence, only point estimates for NPV could be post hoc estimated from the reported information, unclear reference standard, and index test issues (-2 risk of bias).

Negative predictive value subgroup analyses

For the subgroup results, the level of evidence regarding the critical outcome measure negative predictive value was downgraded by two levels to low because of: study limitations including heterogeneity in prevalence, only point estimates for NPV could be post hoc estimated from the reported information, unclear reference standard, and index test issues (-2 risk of bias).

Sensitivity and specificity

The level of evidence regarding the important outcome measure sensitivity was downgraded by one level to moderate because of: study limitations including heterogeneity in prevalence, unclear reference standard, and index test issues (-1 risk of bias).

The level of evidence regarding the important outcome measure specificity was downgraded by one level to moderate because of: study limitations including heterogeneity in prevalence, unclear reference standard, and index test issues (-1 risk of bias).

Zoeken en selecteren

A systematic review of the literature was performed to answer the following two questions:

Subquestion 1: What is the safety and efficiency of diagnostic algorithms consisting of a clinical decision rule, D-dimer and imaging in patients with a suspected first episode or a recurrent episode of deep vein thrombosis (DVT)?

P (Patients):	Adult patients with suspected first episode or relapsed DVT
I (Index test):	Positive outcome clinical decision rule + d-dimer
C (Comparison):	Negative outcome clinical decision rule + d-dimer
R (Reference):	Number of patients with DVT based on compression ultrasonography/Magnetic Resonance Direct Thrombus Imaging or during 3 months follow up
O (Outcomes):	Negative predictive value, sensitivity, specificity
T/S (Timing/setting):	Hospital

Subquestion 2: What is the safety and efficiency of diagnostic algorithms consisting of a clinical decision rule, D-dimer and imaging in patients with a suspected first episode or a recurrent episode of recurrent pulmonary embolism (PE)?

P (Patients):	Adult patients with suspected first episode or relapsed pulmonary embolism
I (Index test):	Positive outcome clinical decision rule + d-dimer
C (Comparison):	Negative outcome clinical decision rule + d-dimer
R (Reference):	Number of patients with pulmonary embolism based on CTPA, V-Q long scan of SPECT, or during 3 months follow up
O (Outcomes):	Negative predictive value, sensitivity, specificity
T/S (Timing/setting):	Hospital

Relevant outcome measures

The guideline development group considered negative predictive value (safety) as a critical outcome measure for decision making, and sensitivity and specificity as important outcome measures for decision making.

A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies.

Per outcome, the working group defined the following minimal clinically important differences:

Negative predictive value (NPV) of ≥97%
Sensitivity of ≥90%
Efficiency/specificity as high as possible

With respect to the NPV, a prevalence dependent cut-off value was applied in the discussion and recommendations, as recommended by the International Society on Thrombosis and Haemostasis (Dronkers, 2021). The combination of a clinical decision rule and a D-dimer test cannot confirm the diagnosis, and follow-up imaging is necessary to do this. Therefore the working group did not a priori define a minimal clinically important difference for efficiency/specificity.

For DVT, the NPV of a diagnostic algorithm in excluding proximal DVT was analysed (distal DVT was not taken into account). Proximal DVT is defined as a DVT at the level of the popliteal vein and/or located more proximal.

Search and select (Methods)

The databases Embase and Ovid/Medline were searched with relevant search terms from 2009 until 15-12-2022. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 508 hits. Studies were selected based on the following criteria:

systematic reviews (searched in at least two databases, and detailed search strategy, risk of bias assessment and results of individual studies available), randomized controlled trials, or observational comparative studies,
full-text English language publication,
adult patients with suspected first episode or relapsed pulmonary embolism or DVT, and
studies according to the PICO.

30 studies were initially selected based on title and abstract screening. After reading the full text, 26 studies were excluded (see the table with reasons for exclusion under the tab Methods), and four studies were included.

Results

Four studies were included in the analysis of the literature. For DVT, two IPD meta-analyses were included. The second IPD meta-analysis by Parpia (2019) is a follow-up that reported on additional outcome measures (sensitivity and specificity) in a subsample of the first IPD meta-analysis (Geersing, 2014). For pulmonary embolism, two systematic reviews and individual-patient data (IPD) meta-analysis were included (Geersing, 2022; Stals 2022). Both studies report comparable results based on similar measures in an almost identical dataset. The two studies complement each other for the outcomes and subgroup analyses of interest for this guideline. Geersing (2022) was used as the main study since it also reports sensitivity and specificity, thus encompassing all outcomes of interest. From Stals (2022), 2 subgroup analyses are included, i.e. patients with cancer and those with suspected recurrent VTE . Important study characteristics and results of the four studies are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.

Referenties

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Dronkers CEA, van der Hulle T, Le Gal G, Kyrle PA, Huisman MV, Cannegieter SC, Klok FA. Toward a tailored diagnostic standard for future diagnostic studies in pulmonary embolism: Communication from the SSC of the ISTH. J Thromb Haemost. 2021 Jul;19(7):1834-1835. doi: 10.1111/jth.15357. PMID: 34176217.
Geersing, G. J., Zuithoff, N. P., Kearon, C., Anderson, D. R., Ten Cate-Hoek, A. J., Elf, J. L., Bates, S. M., Hoes, A. W., Kraaijenhagen, R. A., Oudega, R., Schutgens, R. E., Stevens, S. M., Woller, S. C., Wells, P. S., & Moons, K. G. (2014). Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis. BMJ (Clinical research ed.), 348, g1340. https://doi.org/10.1136/bmj.g1340.
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Evidence tabellen

Evidence table for systematic reviews of diagnostic test accuracy studies

Research question:

Subquestion-1: What is the diagnostic value of clinical decision rules in patients with suspected first episode or relapsed deep vein thrombosis (DVT)?

Subquestion-2: What is the diagnostic value of clinical decision rules in patients with suspected first episode or relapsed pulmonary embolism (PE)?

Study reference

Study characteristics

Patient characteristics

Index test

(test of interest)

Reference test

Follow-up

Outcome measures and effect size

Comments

Geersing, 2022

Study characteristics and results for individual studies are extracted from the SR Geersing, 2022 (unless stated otherwise)

SR and Individual-Patient Data (IPD) meta-analysis

Literature search from 1 January 1995 until 1 November 2021

A: Sanson, 2000

B: Wicki, 2001

C: Perrier, 2004

D: Ghanima, 2005

E: Perrier, 2005

F: van Belle, 2006

G: Goekoop, 2007

H: Righini, 2008

I: Douma, 2011

J: Galipienzo, 2012

K: Mos, 2014

L: Righini, 2014

M: Penaloza, 2017

N: van der Hulle T, 2017

O: Kline, 2002

P: Kearon, 2006

Q: Kline, 2006

R: Runyon, 2007

S: Geersing, 2012

T: Kline, 2012

U: Kline, 2008

V: Schouten, 2014

W: Kearon, 2019

Study design: IPD meta-analysis of studies with a prospective follow-up or cross-sectional design

Setting and Country: Different countries and settings

Source of funding and conflicts of interest:

The study was funded by personal Vidi grant from the Dutch Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

One author received grants from several pharmaceutical companies, the Dutch thrombosis association, The Netherlands Organisation for Health Research and Development and the Dutch Heart foundation. One author has participated in advisory boards from several pharmaceutical companies, receive lecture honoraria and grants from several pharmaceutical companies.

Inclusion criteria SR: patients with clinically suspected PE, at least 1 of the clinical decision rules (CDRs) of interest assessed and as a reference standard: imaging or clinical follow-up for those not receiving anticoagulant treatment.

Exclusion criteria SR: More than 80% missing data for variables necessary for imputation (5 studies excluded for >80% missing D-dimer data)

23 studies were included in the IPDA meta-analysis with 14 studies in the referred secondary care setting (A-N).

Important patient characteristics:

	N	PE, n (%)	Care setting
Total	35 248	1864 (19%)	Mix
Included	17 052	20%	Referred secondary care
A	517	517 (30.9%)	Referred secondary care and inpatients
B	1089	1089 (27.2%)	Referred secondary care
C	965	965 (23.7%)	Referred secondary care
D	432	432 (22.0%)	Referred secondary care
E	755	755 (26.1%)	Referred secondary care
F	3296	3296 (21.2%)	Referred secondary care and inpatients
G	876	876 (12.6%)	Referred secondary care
H	1692	1692 (21.3%)	Referred secondary care
I	807	807 (23.8%)	Referred secondary care and inpatients
J	240	240 (26.3%)	Referred secondary care
K	279	279 (40.9%)	Referred secondary care and inpatients
L	3324	3324 (19.2%)	Referred secondary care
M	705	705 (21.7%)	Referred secondary care
N	3448	3448 (13.7%)	Referred secondary care and inpatients
O	948	948 (19.6%)	Self-referral emergency care
P	1123	1123 (15.0%)	Primary healthcare and inpatients
Q	2255	2255 (4.8%)	Self-referral emergency care
R	1187	1187 (3.3%)	Self-referral emergency care
S	597	597 (12.2%)	Primary healthcare
T	678	678 (17.0%)	Self-referral emergency care and inpatients
U	7889	7889 (7.1%)	Self-referral emergency care
V	129	129 (39.8%)	Primary healthcare and nursing homes
W	2017	2017 (7.4%)	Primary healthcare and inpatients

IPD meta-analysis: Several diagnostic strategies were compared.

Clinical decision rules included the Wells score, revised Geneva score, and the YEARS algorithm.

The D-dimer threshold was either fixed (500 μg/L), age-adjusted (age x 10 μg/L in patients aged >50 years) or dependent on pretest probability (PPT) for Wells and Geneva. For the PTP adjusted D-dimer levels low probability (Wells score of ≤4 or Geneva score of ≤5) has a D-dimer cut-off of 1000 ng/ml and moderate probability (score of ≥6) has a D-dimer cut-off of 500 ng/ml. In the YEARS algorithm the D-dimer threshold is dependent on clinical pretest probability (CPTP) assessment (with a higher D-dimer threshold for patients with a low CPTP).

Imaging or clinical follow-up in those in whom PE was ruled out without imaging and who thus did not receive anticoagulant treatment.

Prevalence (%)

[based on refence test at specified cut-off point]

A: 30.9

B: 27.2

C: 23.7

D: 22.0

E: 26.1

F: 21.2

G: 12.6

H: 21.3

I: 23.8

J: 26.3

K: 40.9

L: 19.2

M: 21.7

N: 13.7

O: 19.6

P: 15.0

Q: 4.8

R: 3.3

S: 12.2

T: 17.0

U: 7.1

V: 39.8

W: 7.4

Complete data:

Unclear from the information provided in the study for how many participants complete outcome data was available.

Authors include % missing data per variable. This indicates no missing data for VTE diagnosis at baseline or follow-up except for study E (Schouten, 2014) with 0.3% missing values. No reason was given for the missing values.

In case of missing values in the diagnostic strategies and outcomes, imputation was used. Multilevel chained equations included all items in the diagnostic strategies and the outcome. Ten imputation data sets were created, and the analysis results were combined using the Rubin rule.

All studies had 3 months follow-up periods.

Negative predictive value (NPV) can be post hoc estimated from the two outcomes measures reported by the authors:

Diagnostic failure rate: “the predicted 3-month VTE incidence after exclusion of PE without imaging at baseline.” (= false negatives)
Efficiency: “the proportion of individuals classified by the strategy as PE considered excluded without imaging tests” (True negatives plus false negatives)

Point estimates as well as 95% prediction intervals (CI) were given.

NPV point estimates and 95% CI were calculated with: as following: NPV = 1 -failure rate.

Clinical decision rule	Failure rate	Efficiency	NPV
Wells + any D-dimer	0.75 (95%CI 0.50 to 1.13)	29.57 (95%CI 25.39 to 34.12)	98.6
Wells + D-dimer <500 μg/L	0.32 (95%CI 0.17 to 0.60)	27.77 (95%CI 23.05 to 33.03)	98.6
Wells + age-adjusted D-dimer	0.65 (95%CI 0.43 to 0.99)	32.91 (95%CI 27.85 to 38.39)	97.6
Wells + PTP D-dimer	3.06 (95%CI 2.47 to 3.78)	48.78 (95%CI 43.64 to 53.94)	97.6
Geneva + any D-dimer	1.17 (95%CI 0.79 to 1.74)	30.46 (95%CI 26.75 to 34.44)	98.1
Geneva + D-dimer <500 μg/L	0.37 (95%CI 0.19 to 0.74)	28.77 (95%CI 26.20 to 31.48)	98.1
Geneva + age-adjusted D-dimer	0.81 (95%CI 0.51 to 1.27)	35.25 (95%CI 32.76 to 37.82)	97.0
Geneva + PTP D-dimer	2.95 (95%CI 2.34 to 3.71)	43.02 (95%CI 38.28 to 47.31)	97.0
YEARS	2.10 (95%CI 1.59 to 2.75)	43.38 (95%CI 38.86 to 48.01)	95.6

Sensitivity and specificity

Clinical decision rule	Sensitivity	Specificity
Wells + any D-dimer	98.38 (95%CI 95.87 to 99.41)	36.89 (95%CI 32.53 to 41.47)
Wells + D-dimer <500 μg/L	99.59 (95%CI 99.10 to 99.82)	35.21 (95%CI 30.19 to 40.57)
Wells + age-adjusted D-dimer	98.93 (95%CI 98.15 to 99.39)	41.58 (95%CI 36.42 to 46.93)
Wells + PTP D-dimer	93.25 (95%CI 91.91 to 94.38)	60.80 (95%CI 56.24 to 65.19)
Geneva + any D-dimer	97.75 (95%CI 93.86 to 99.27)	39.25 (95%CI 34.57 to 44.14)
Geneva + D-dimer <500 μg/L	99.53 (95%CI 98.88 to 99.80)	37.23 (95%CI 34.00 to 40.57)
Geneva + age-adjusted D-dimer	98.51 (95%CI 97.37 to 99.16)	45.27 (95%CI 42.63 to 47.95)
Geneva + PTP D-dimer	98.51 (95%CI 97.37 to 99.16)	45.27 (95%CI 42.63 to 47.95)
YEARS	94.18 (95%CI 92.70 to 95.38)	54.49 (95%CI 50.82 to 58.12)

Study quality (ROB): QUADAS-2 was used to report risk of bias per individual study. Most studies had low risk of bias and applicability concerns, with most common being an unclear risk of bias for the reference standard (four studies: B, C, E, G).

C and E were the only two studies with high risk of patient selection and index test. M also had unclear risk of bias in the index test. For the index test there is also unclear (study M) or high (studies C and E) applicability concerns. Finally risk of bias in flow and timing was high for studies C and D and unclear for study M.

Place of the index test in the clinical pathway: replacement of scan.

Choice of cut-off point: Important to reliably exclude individuals for further diagnostic testing with (expensive) scans while identifying all relevant patients. Thus, interested in a high number of true negatives and a low number of false negatives. The 500 μg/L threshold has less false negatives but results in more scans. The age-adjusted D-dimer threshold and YEARS algorithm set higher D-dimer threshold depending on age or clinical information to avoid unnecessary testing.

The authors conclude that all strategies have acceptable safety (low predicted failure rates). Efficiency was higher for adapted D-dimer thresholds.

To avoid exclusion of entire studies, 1-stage multilevel chained equations were used to impute missing values. Multilevel chained equations included all items in the diagnostic strategies and the outcome. Ten imputation data sets were created, and the analysis results were combined using the Rubin rule.

Subgroup analyses were done by sex, age, cancer, and previous venous thromboembolism (VTE).

A sensitivity analysis was performed including only studies with data on all diagnostic strategies. This resulted in similar failure rate and efficiency estimates (see table below).

Clinical decision rule	Failure rate	Efficiency
Wells + D-dimer <500 μg/L	0.32 (95%CI 0.09 to 0.91)	23.72 (95%CI 20.17 to 27.68)
Wells + age-adjusted D-dimer	0.50 (95%CI 0.27 to 0.92)	28.86 (95%CI 24.82 to 33.26)
Wells + PTP D-dimer	3.02 (95%CI 2.32 to 3.92)	45.83 (95%CI 41.27 to 50.46)
Geneva + D-dimer <500 μg/L	0.40 (95%CI 0.19 to 0.83)	28.73 (95%CI 25.63 to 32.05)
Geneva + age-adjusted D-dimer	0.72 (95%CI 0.43 to 1.21)	35.23 (95%CI 32.26 to 38.32)
Geneva + PTP D-dimer	2.88 (95%CI 2.22 to 3.74)	43.05 (95%CI 37.94 to 48.32)
YEARS	2.02 (95%CI 1.42 to 2.85)	40.33 (95%CI 36.94 to 43.82)

Stals, 2022

Study characteristics and results for individual studies are extracted from the SR Stals, 2022 (unless stated otherwise)

SR and Individual-Patient Data (IPD) meta-analysis

Literature search from 1 January 1995 until 1 January 2021

A: Kline, 2012

B: Douma, 2011

C: Goekoop, 2007

D: Righini, 2014

E: Schouten, 2014

F: van Belle, 2006

G: Van der Hulle, 2017

H: Mos, 2014

I: Wicki, 2001

J: Perrier, 2004

K: Perrier, 2005

L: Righini, 2008

M: Kearon, 2019

N: Galipienzo, 2012

O: Ghanima, 2005

P: Penaloza, 2017

Study design: IPD meta-analysis of studies with a prospective follow-up or cross-sectional design

Setting and Country: Different countries, but in hospital patients (mostly outpatients, but some inpatients included)

Source of funding and conflicts of interest:

The study was funded by the Dutch Research Council. The sponsor was not involved in the study and the authors had final responsibility for study design, oversight, data verification, analyses and accuracy and completeness of the manuscript. Two authors disclosed receiving personal fees for consulting and payment or honoraria for educational events such as presentations from Sobi, Pfizer, UCB, Argenx, Amgen, Sanofi, Bayer, Novartis in the 36 months preceding publication of the study.

Exclusion criteria SR: only qualitative D-dimer measurements performed and patients with only low clinical pretest probability.

16 studies included

Important patient characteristics:

	N	Median Age (IQR), yrs	Female, n (%)	Inpatients, n (%)	Previous VTE, n (%)	Tachycardia, n (%)
Overall	20 553	58 (43–71)	12 161 (59)	1606 (7.8)	2941 (14)	4383 (21)
A	334	57 (47–66)	200 (60)	334 (100)	50 (15)	60 (18)
B	807	54 (40–67)	487 (60)	163 (20)	39 (4.8)	184 (23)
C	876	50 (38–65)	549 (63)	0 (0)	84 (9.6)	166 (19)
D	3324	63 (53–73)	1887 (57)	0 (0)	466 (14)	722 (22)
E	294	76 (67–84)	195 (66)	0 (0)	52 (18)	64 (22)
F	3296	52 (39–68)	1897 (58)	605 (18)	427 (13)	690 (21)
G	3448	54 (40–67)	2142 (62)	468 (14)	360 (10)	693 (20)
H	279	54 (42–68)	164 (59)	36 (13)	279 (100)	59 (21)
I	1089	62 (46–76)	597 (55)	0 (0)	202 (19)	236 (22)
J	965	63 (45–77)	562 (58)	0 (0)	167 (17)	186 (19)
K	1692	61 (45–75)	923 (55)	0 (0)	300 (18)	369 (22)
L	755	63 (45–76)	453 (60)	0 (0)	142 (19)	176 (23)
M	2017	53 (38–66)	1335 (66)	1 (0)	164 (8.1)	398 (20)
N	240	67 (54–78)	122 (51)	0 (0)	38 (16)	56 (23)
O	432	58 (43–73)	231 (54)	0 (0)	44 (10)	79 (18)
P	705	61 (46–76)	419 (59)	0 (0)	127 (18)	246 (35)

IPD meta-analysis: Several diagnostic strategies were compared.

Clinical decision rules included the Wells score, revised Geneva score, and the YEARS algorithm.

The D-dimer threshold was either fixed (500 μg/L) or age-adjusted (age x 10 μg/L in patients aged >50 years) for Wells and Geneva. In the YEARS algorithm the D-dimer threshold is dependent on clinical pretest probability (CPTP) assessment (with a higher D-dimer threshold for patients with a low CPTP).

Per study:

A: Wells score and revised Geneva score with D-dimer threshold 1000 μg/L for “PE unlikely” patients

B: Wells rule and revised Geneva score (both original and simplified version) with D-dimer testing (threshold, 500 μg/L). All four CDRs negative for PE to be unlikely.

C: Dichotomized Wells score combined with D-dimer testing (threshold, 500 μg/L)

"D: Wells or revised Geneva score combined with D-dimer testing (threshold of 500 μg/L in patients aged

<50 y and age-adjusted threshold in patients aged ≥50 y) "

E: Wells score with D-dimer testing (set-up with qualitative assay, but quantitative data was collected in 50% of the participants)

F: Dichotomized Wells score combined with D-dimer testing (threshold, 500 μg/L)

G: YEARS score with D-dimer (threshold, 1000 μg/L if 0 YEARS items and 500 μg/L if 1–3 YEARS items)

H: Dichotomized Wells score combined with D-dimer testing (threshold, 500 μg/L)

I: Geneva score with D-dimer testing

J: Geneva score with D-dimer testing (threshold, 500 μg/L)

K: Geneva score with D-dimer testing (threshold, 500 μg/L)

L: Geneva score with D-dimer testing (threshold, 500 μg/L)

M: Wells score with D-dimer testing (threshold, 1000 μg/L for low clinical probability and 500 μg/L for moderate clinical probability)

N: Dichotomized Wells score combined with D-dimer testing (threshold, 500 μg/L)

O: Algorithm based on the Hyers criteria combined with D- dimer testing (threshold, 400 μg/L)

P: Pulmonary embolism rule-out criteria (PERC) with D-dimer testing

Imaging or clinical follow-up in those in whom PE was ruled out without imaging and who thus did not receive anticoagulant treatment.

Reference test and cut-off point(s):

A: CTPA or 30 days clinical follow-up

B: CTPA or 3 months clinical follow-up

C: CTPA or V/Q or 3 months clinical follow-up

D: CTPA or 3 months clinical follow-up

E: CTPA or V/Q or 3 months clinical follow-up

F: CTPA or 3 months clinical follow-up

G: CTPA or 3 months clinical follow-up

H: CTPA or 3 months clinical follow-up

I: Lung scan

J: CTPA or 3 months clinical follow-up

K: Multidetector

row CT

and CUS or 3 months clinical follow-up

L: CTPA or 3 months clinical follow-up

M: CTPA or 3 months clinical follow-up

N: CTPA or 3 months clinical follow-up

O: MSCTor 3 months clinical follow-up

P: CTPA or V/Q or 3 months clinical follow-up

Prevalence (%)

[based on refence test at specified cut-off point]

A: 23

B: 24

C: 13

D: 19

E: 28

F: 21

G: 14

H: 41

I: 27

J: 24

K: 21

L: 26

M: 7,4

N: 26

O: 22

P: 22

Complete data:

Unclear from the information provided in the study for how many participants complete outcome data was available.

Only A (Kline 2012) had a follow-up of 30 days, all other studies had 3 months follow-up periods.

Not enough information was provided to report on sensitivity or specificity.

Negative predictive value (NPV) can be post hoc estimated from the two outcomes measures reported by the authors:

Diagnostic failure rate: “the predicted 3-month VTE incidence after exclusion of PE without imaging at baseline.” (= false negatives)
Efficiency: “the proportion of individuals classified by the strategy as PE considered excluded without imaging tests” (True negatives plus false negatives)

Point estimates as well as 95% prediction intervals (CI) were given.

NPV point estimates and 95% CI were calculated as following: NPV = 1 -failure rate.

Wells plus fixed D-dimer

NPV point estimate = (26-0.36)/26 = 0.986

NPV 95% CI = 0.981-0.987

Wells plus age-adjusted D-dimer

NPV point estimate = (32-0.76)/32 = 0.976

NPV 95% CI = 0.969 - 0.978

YEARS

NPV point estimate = (41-1.8)/41= 0.956

NPV 95% CI = 0.934-0.965

J and K were the only two studies with high risk of patient selection and index test. A and P also had unclear risk of bias in the index test. For the index test there is also unclear (study P) or high (studies J and K) applicability concerns. Finally risk of bias in flow and timing was high for studies O and J and unclear for study M.

Place of the index test in the clinical pathway: replacement of scan.

The authors conclude that all strategies have acceptable safety (low predicted failure rates). Efficiency was higher for adapted D-dimer thresholds.

To avoid exclusion of entire studies, 1-stage multilevel chained equations were used to impute missing values (including systematically missing values). Multilevel chained equations included all items in the diagnostic strategies and the outcome. Ten imputation data sets were created, and the analysis results were combined using the Rubin rule.

Subgroup analyses were done by sex, age, cancer, and previous venous thromboembolism (VTE).

VTE detected during follow-up could be a new event and thus unrelated to the index presentation. The authors performed a sensitivity analysis in which only VTE events diagnosed at baseline with imaging was used as the outcome. This sensitivity analysis resulted in slightly lower point estimates for failure rate.

Heterogeneity: In general, patient characteristics and reference specification were similar. There is heterogeneity in the availability and definition of items included in the diagnostic strategies. Most studies used Wells rules or collected these variables based on Geneva scoring items. Various D-dimer assays were used and D-dimer threshold can vary between studies, most used >500 μg/L. For the IPD meta-analysis raw D-dimer assay data was used to calculate estimates based on the D-dimer thresholds specified by the authors. The authors made forest plots and gave I2 statistics for the subgroup analyses. Based on these forest plots there was considerable between study heterogeneity for both failure rate and efficiency of each diagnostic strategy. With wider confidence intervals for patients with cancer and patients with a history of VTE.

Geersing, 2014

Study characteristics and results for individual studies are extracted from the SR Geersing, 2014 (unless stated otherwise)

IPD meta-analysis

Literature search from 2006 to supplement studies from previous meta-analysis

A: Anderson 2000

B: Kraaijenhagen 2002

C: Schutgens 2003

D: Wells 2003

E: Elf 2009

F: Kearon 2001

G: Anderson 2003

H: Bates 2003

I: Stevens 2004

J: Kearon 2005

K: Oudega 2005

L: Toll 2006

M: AMUSE study 2009

Study design: IPD meta-analysis of studies with a prospective follow-up design

Setting and Country: 13 studies in Canada, the Netherlands, the United States, and Sweden. Outpatients in the primary and hospital setting (with subgroup analysis for care setting)

Source of funding and conflicts of interest:

The study received no funding. The authors declare: “no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.”

Inclusion criteria SR: consecutive outpatients with suspected DVT; have the results of any D-dimer testing before reference testing; data on all predictors that form the Wells rule; categorised patients with the Wells rule before venous imaging (reference test); document the presence or absence of proximal DVT by an acceptable reference test.

Exclusion criteria SR: None mentioned (besides the inclusion criteria). For the current guideline only studies in the secondary/hospital patients were included.

13 studies were included in the IPDA meta-analysis with 10 studies in the hospital outpatient setting (A-J).

Important patient characteristics:

Of the 10 002 patients in the IPD meta-analysis, 1864 (19%) had proximal DVT. The median age was 59 years and 62% of patients were female.

	N	DVT, n (%)	Care setting	D-dimer	Inclusion
Total	10 002	1864 (19%)	Mix	Mix	no
Included	4511	unknown	Hospital	yes	Yes
A	153	26 (17)	Hospital	yes	yes
B	1756	411 (23)	Hospital	yes	yes
C	814	318 (39)	Hospital	yes	yes
D	541	121 (22)	Hospital	yes	yes
E	325	52 (16)	Hospital	yes	yes
F	429	61 (14)	Hospital	no	no
G	1075	190 (18)	Hospital	no	no
H	550	55 (10)	Hospital	no	no
I	436	42 (10)	Hospital	no	no
J	809	42 (5)	Hospital	no	no
K	1295	289 (22)	Primary	yes	no
L	791	126 (16)	Primary	yes	no
M	1028	131 (13)	Primary	yes	no

A low score on the Wells rule (≤1) combined with a negative D-dimer test (quantitative or qualitative).

For quantitative D-dimer assays the cut-off as reported in the original study was used (most studies <500 µg/L). For qualitative D-dimer (point of care) assays, only a positive or negative test result was reported.

Reference tests were either compression ultrasonography (CUS) or venography at initial presentation, or, if venous imaging was not performed, an uneventful follow-up for at least three months.

Reference test and cut-off point(s):

A: CUS or venography at baseline or 3 months uneventful follow-up

B: CUS at baseline or 3 months uneventful follow-up

C: CUS at baseline or 3 months uneventful follow-up

D: CUS at baseline or 3 months uneventful follow-up

E: CUS or venography at baseline or 3 months uneventful follow-up

Prevalence (%)

[based on refence test at specified cut-off point]

A: 17

B: 23

C: 39

D: 22

E: 16

For how many participants were no complete outcome data available?

In all studies complete outcome data was available, except for study B (Kraaijenhagen 2002) with 3% missing values for DVT.

No reason was given for the missing values.

In case of missing values in the diagnostic tests (D-dimer and any predictors included in the Wells rule), reference tests or DVT outcome, imputation with multivariable regression was used. Imputation was done per dataset, therefore studies without data on D-dimer testing were not included in the results. It is unclear how many imputation data sets were created.

All studies had a minimal follow-up of three months.

Not enough information was provided to report on sensitivity or specificity.

Negative predictive value (NPV) can be post hoc estimated from the two outcomes measures reported by the authors:

Diagnostic failure rate: the predicted 3-month DVT incidence after exclusion of DVT without imaging at baseline. (= false negatives)
Efficiency: the proportion of individuals classified DVT excluded based on scoring ≤1 on the Wells rule and a negative D-dimer test (=True negatives plus false negatives)

Point estimates as well as 95% prediction intervals (CI) were given.

NPV point estimates and 95% CI were calculated as following: NPV = 1 -failure rate.

Wells ≤1 plus negative D-dimer

Failure rate: 0.9% (95%CI 0.0 to 1.9)

Efficiency: 23.1% (95%CI 12.8 to 38.3)

NPV: 96.1% (95%CI 95 to 100%)

Study quality (ROB): The authors provide limited information about study quality. Many of the included studies did not explicitly blind of the outcome (DVT) assessor to the results of the Wells rule and D-dimer testing. This can lead to an overoptimistic estimate of the value of the Wells rule and D-dimer testing for assessing DVT.

Place of the index test in the clinical pathway: replacement of scan.

Choice of cut-off point:

Important to reliably exclude individuals for further diagnostic testing with (expensive) scans. Thus, interested in a high number of true negatives and low number of false positives.

Heterogeneity: There was considerable heterogeneity between the studies in prevalence estimates. This likely contributed to the relatively wide prediction intervals calculated by the authors. The main analyses were repeated with prevalence set at 15% (a prevalence that best reflects a European or primary care based healthcare setting). But this was not done for the secondary analysis for care setting that was reported in in this guideline, so it is unclear how the heterogeneity in prevalence between studies affected the results.

Parpia, 2019

Study characteristics and results for individual studies are extracted from the SR Geersing, 2024 (unless stated otherwise)

IPD meta-analysis

Literature search from 1 January 1995 until 1 January 2021

C: Schutgens 2003

L: Toll 2006

E: Elf 2009

N: Linkins 2013

Study design: prospective follow-up

Setting and Country: 4 studies; one in Canada, two in the Netherlands, and one in Sweden. Outpatient setting with three studies in hospital and one in primary care.

Source of funding and conflicts of interest:

The study was funded by Hamilton Health Sciences New Investigator Fund. Dr Kearon is supported by the Jack Hirsh Professorship in Thromboembolim. Dr Geersing is supported by a Veni and Vidi from the Dutch Research Council (NWO/ZonMw).All authors declared no conflicts of interest.

Inclusion criteria SR: consecutive outpatients with suspected DVT; have the results of a quantitative D-dimer test before reference testing; data on all predictors that form the Wells rule; categorised patients with the Wells rule before venous imaging (reference test); document the presence or absence of proximal DVT by an acceptable reference test.

Exclusion criteria SR: Patients with a high clinical pre-test probability (CPTP) based on the Wells score were excluded as D-dimer is not recommended to exclude DVT in these patients. 814 of 3368 patients were excluded for this reason.

4 studies were included.

Important patient characteristics:

Of the 3368 patients in the four studies, 814. 2254 patients with low or moderate CPTP were included in the analysis. A DVT diagnosis was present in 12% of all patients, prevalence varied from 5% to 31% between studies. 64% of all patients were female, the mean age was 59 years and 44% had low CPTP.

	C	L	E	N	Total
N	517	443	274	1320	2554
DVT: n (%)	162 (31)	48 (11)	25 (9)	61 (5)	296 (12)
Age: mean (SD)	58 (17)	59 (17)	58 (17)	60 (16)	59 (17)
Female: n (%)	332 (64)	278 (63)	169 (62)	848 (64)	1627 (64)
Active cancer: n (%)	28 (5)	14 (3)	4 (1)	62 (5)	108 (4)
Bedridden: n (%)	24 (5)	21 (5)	5 (2)	94 (7)	144 (6)
Paresis: n (%)	5 (1)	31 (7)	8 (3)	34 (3)	78 (3)
Calf swelling: n (%)	111 (21)	97 (22)	51 (19)	137 (10)	396 (16)
Leg swelling: n (%)	47 (9)	109 (25)	17 (6)	84 (6)	257 (10)
Tenderness: n (%)	284 (55)	277 (62)	125 (46)	580 (44)	1266 (50)
Pitting edema: n (%)	181 (35)	193 (44)	59 (22)	293 (22)	726 (28)
Dilated vein: n (%)	37 (7)	50 (11)	25 (9)	50 (4)	162 (6)
Alternative diagnosis: n (%)	196 (38)	232 (52)	114 (42)	547 (41)	1089 (43)
Wells 0: n (%)	195 (38)	95 (21)	151 (55)	693 (53)	1134 (44)
Wells 1-2: n (%)	322 (62)	348 (79)	123 (45)	627 (48)	1420 (56)
D-dimer assay	Tinaquant	VIDAS/ Tinaquant	Auto dimer	Triage
Country	Netherlands	Netherlands	Sweden	Canada	–
Care setting	Secondary	Primary	Secondary	Secondary	–

A low score on the Wells rule (≤1) combined with a negative D-dimer test (quantitative or qualitative).

Reference tests were either compression ultrasonography (CUS) or venography at initial presentation, or, if venous imaging was not performed, an uneventful follow-up for at least three months.

Reference test and cut-off point(s):

A: CUS or venography at baseline or 3 months uneventful follow-up

B: CUS at baseline or 3 months uneventful follow-up

C: CUS at baseline or 3 months uneventful follow-up

D: CUS at baseline or 3 months uneventful follow-up

E: CUS or venography at baseline or 3 months uneventful follow-up

Prevalence (%)

[based on refence test at specified cut-off point]

C: 31

L: 11

E: 25

N: 61

For how many participants were no complete outcome data available?

Unclear. Authors mention few patients were lost to follow-up, but do not provide a numerical indication nor any reasons for loss to follow-up.

All studies had a minimal follow-up of three months.

Table gives point estimates (95% CI).

D-dimer

Efficiency

NPV

Sensitivity

Specificity

<500 μg/L

38.9

(29.1-48.7)

99.8

(99.5- 100)

99.0

(97.8- 100.0)

45.2

(39.6- 50.9)

age x 10 μg/L for >50 years

47.4

(35.3- 59.3)

99.7

(99.4- 100.0)

98.0

(96.3- 99.5)

54.7

(48.3- 61.2)

Study quality (ROB):The authors provide limited information about quality of the included studies.

Place of the index test in the clinical pathway: replacement of scan.

Choice of cut-off point:

Important to reliably exclude individuals for further diagnostic testing with (expensive) scans. Thus, interested in a high number of true negatives and low number of false positives.

Heterogeneity: studies differed in prevalence of DVT and distribution of patients in Wells 0 or 1-2. Having a smaller proportion of patients in the 0 Wells group reduces specificity and the amount of patients testing negative.

In addition, different D-dimer assays (three latex agglutination assays and one enzyme-linked immunosorbent assays [ELISA]) were used in different settings (three studies in secondary setting, one study in primary care setting).

Table of quality assessment for systematic reviews of diagnostic studies

Research question:

Subquestion-1: What is the diagnostic value of clinical decision rules in patients with suspected first episode or relapsed deep vein thrombosis (DVT)?

Subquestion-2: What is the diagnostic value of clinical decision rules in patients with suspected first episode or relapsed pulmonary embolism (PE)?

Study First author, year	Appropriate and clearly focused question? Yes/no/unclear	Comprehensive and systematic literature search? Yes/no/unclear	Description of included and excluded studies? Yes/no/unclear	Description of relevant characteristics of included studies? Yes/no/unclear	Assessment of scientific quality of included studies? Yes/no/unclear	Enough similarities between studies to make combining them reasonable? Yes/no/unclear	Potential risk of publication bias taken into account? Yes/no/unclear	Potential conflicts of interest reported? Yes/no/unclear
Geersing, 2022	Yes, “to assess the capability of ruling out PE by available diagnostic strategies across all possible settings.”	Yes, “MEDLINE was first searched from January 1, 1995 to August 25, 2016 (this was recently updated until November 1, 2021)”. Full description available as appendix in the protocol registration.	Yes, potentially relevant studies that are excluded at final selection (after reading the full text) are referenced in text with reasons.	Unclear, characteristics related to PICO such as patient population, type of clinical decision rule and D-dimer test, reference and timing/setting are described. Although type of clinical decision rule was only described overall, not available for each individual study.	Yes, authors assessed studies using the QUADAS-2, reported risk of bias with +/?/-and took this into account in the evidence synthesis. They do not specify the reasons for lower ratings in individual studies. Therefore, it is not possible to reproduce their QUADAS-2 rating per study.	Yes	No, the potential risk of publication bias is not discussed.	No, source of funding SR is clear but not for individual studies.
Stals, 2022	Yes, “To evaluate the safety and efficiency of the Wells and revised Geneva scores combined with fixed and adapted D-dimer thresholds, as well as the YEARS algorithm, for ruling out acute pulmonary embolism (PE) in relevant patient subgroups defined by sex, age, cancer, and previous venous thromboembolism (VTE)”	Yes, “MEDLINE was searched from 1 January 1995 until 1 January 2021 to retrieve studies that had evaluated diagnostic strategies for PE”. Full description available as appendix.	Yes, potentially relevant studies that are excluded at final selection (after reading the full text) are referenced in text with reasons.	Yes, characteristics related to PICO such as patient population, type of clinical decision rule and D-dimer test, reference and timing/setting are described.	Unclear, authors assessed studies using the QUADAS-2 and reported risk of bias with +/?/-, but do not take this into account in the evidence synthesis. They do not specify the reasons for lower ratings in individual studies. Therefore, it is not possible to reproduce their QUADAS-2 rating per study.	Yes	No, the potential risk of publication bias is not discussed.	No, source of funding SR is clear but not for individual studies.
Geersing, 2014	Yes, “To assess the accuracy of the Wells rule for excluding deep vein thrombosis and whether this accuracy applies to different subgroups of patients.”	Unclear, authors updated the search from a previous meta-analysis by searching for additional papers after 2006 with a validated algorithm for finding diagnostic studies. Full description search algorithm available as supplement. However, unclear which databases were searched.	Yes, potentially relevant studies that are excluded at final selection (after reading the full text) are specified in the supplement.	Yes, description characteristics related to PICO such as patient population, application Wells rule and D-dimer test, reference and timing/setting.	No, authors discuss methodological considerations in the discussion but did not use a quality scoring tool or checklist.	Unclear, there was considerable heterogeneity in study prevalence (ranging 5-39%) for the main analysis (including both primary and secondary care settings). A sensitivity analysis was done for the main analysis to assess the influence of prevalence. However, in the current guideline results from a secondary analysis are used for the hospital setting only (prevalence ranging 16-39%).	No, the potential risk of publication bias is not discussed.	No, source of funding SR is clear but not for individual studies.

Risk of bias assessment diagnostic accuracy studies (QUADAS II, 2011)

Research question:

Subquestion-1: What is the diagnostic value of clinical decision rules in patients with suspected first episode or relapsed deep vein thrombosis (DVT)?

Subquestion-2: What is the diagnostic value of clinical decision rules in patients with suspected first episode or relapsed pulmonary embolism (PE)?

Study reference	Patient selection	Index test	Reference standard	Flow and timing	Comments with respect to applicability
Geersing, 2022	Was a consecutive or random sample of patients enrolled? Yes, only prospective follow-up or cross-sectional studies were included in the individual patient level meta-analysis. Was a case-control design avoided? Yes Did the study avoid inappropriate exclusions? Yes	Were the index test results interpreted without knowledge of the results of the reference standard? Yes If a threshold was used, was it pre-specified? Yes	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? Unclear, the reference test was always done after the index test and likely part of the patient record.	Was there an appropriate interval between index test(s) and reference standard? Yes Did all patients receive a reference standard? Yes, part of the reference standard was clinical follow-up but not all patients underwent imaging procedures. Did patients receive the same reference standard? No Were all patients included in the analysis? Yes, authors used multiple imputation for missing values but do not report whether there were follow-up issues in the original study.	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
CONCLUSION: Could the selection of patients have introduced bias? RISK: LOW	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: LOW	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: UNCLEAR	CONCLUSION Could the patient flow have introduced bias? RISK: UNCLEAR
Stals, 2022	Was a consecutive or random sample of patients enrolled? Yes, only prospective follow-up or cross-sectional studies were included in the individual patient level meta-analysis. Was a case-control design avoided? Yes Did the study avoid inappropriate exclusions? Yes	Were the index test results interpreted without knowledge of the results of the reference standard? Yes If a threshold was used, was it pre-specified? Yes	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? Unclear, the reference test was always done after the index test and likely part of the patient record. Nine studies adjudicated outcomes and three studies adjudicated deaths, but four studies did not adjudicate outcomes.	Was there an appropriate interval between index test(s) and reference standard? Yes Did all patients receive a reference standard? Yes, part of the reference standard was clinical follow-up but not all patients underwent imaging procedures. Did patients receive the same reference standard? No Were all patients included in the analysis? Yes, authors used multiple imputation for missing values but do not report whether there were follow-up issues in the original study.	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
CONCLUSION: Could the selection of patients have introduced bias? RISK: LOW	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: LOW	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: UNCLEAR	CONCLUSION Could the patient flow have introduced bias? RISK: UNCLEAR
Geersing, 2014	Was a consecutive or random sample of patients enrolled? Yes Was a case-control design avoided? Yes Did the study avoid inappropriate exclusions? Yes	Were the index test results interpreted without knowledge of the results of the reference standard? Yes If a threshold was used, was it pre-specified? Yes, but for D-dimer testing both a qualitative and quantitative assay was used. With a mix of thresholds for the quantitative assays (the threshold used within the study)	Is the reference standard likely to correctly classify the target condition? Yes, although CUS is less able to identify recurrent events, notably ipsilateral ones. Were the reference standard results interpreted without knowledge of the results of the index test? No, in some studies DVT assessors were not blinded.	Was there an appropriate interval between index test(s) and reference standard? Yes Did all patients receive a reference standard? Yes Did patients receive the same reference standard? No part of the reference standard was clinical follow-up but not all patients underwent imaging procedures. Were all patients included in the analysis? Yes, authors used multiple imputation for missing values but do not report whether there were follow-up issues in the original study.	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: LOW	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: HIGH	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: HIGH	CONCLUSION Could the patient flow have introduced bias? RISK: UNCLEAR
Parpia, 2019	Was a consecutive or random sample of patients enrolled? Yes Was a case-control design avoided? Yes Did the study avoid inappropriate exclusions? No, excluded patients with Wells score >2 which can result in higher NPV (critical outcome).	Were the index test results interpreted without knowledge of the results of the reference standard? Yes If a threshold was used, was it pre-specified? Yes	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? No, in some studies DVT assessors were not blinded.	Was there an appropriate interval between index test(s) and reference standard? Yes Did all patients receive a reference standard? Yes Did patients receive the same reference standard? No part of the reference standard was clinical follow-up but not all patients underwent imaging procedures. Were all patients included in the analysis? Unclear, authors do not report whether there were follow-up issues and did not use imputation.	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: HIGH	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: LOW	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: HIGH	CONCLUSION Could the patient flow have introduced bias? RISK: UNCLEAR

Study reference

Patient selection

Index test

Reference standard

Flow and timing

Comments with respect to applicability

Geersing, 2022

Was a consecutive or random sample of patients enrolled?

Yes, only prospective follow-up or cross-sectional studies were included in the individual patient level meta-analysis.

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Yes

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear, the reference test was always done after the index test and likely part of the patient record.

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes, part of the reference standard was clinical follow-up but not all patients underwent imaging procedures.

Did patients receive the same reference standard?

Were all patients included in the analysis?

Yes, authors used multiple imputation for missing values but do not report whether there were follow-up issues in the original study.

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: LOW

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: UNCLEAR

CONCLUSION

Could the patient flow have introduced bias?

RISK: UNCLEAR

Stals, 2022

Was a consecutive or random sample of patients enrolled?

Yes, only prospective follow-up or cross-sectional studies were included in the individual patient level meta-analysis.

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Yes

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear, the reference test was always done after the index test and likely part of the patient record. Nine studies adjudicated outcomes and three studies adjudicated deaths, but four studies did not adjudicate outcomes.

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes, part of the reference standard was clinical follow-up but not all patients underwent imaging procedures.

Did patients receive the same reference standard?

Were all patients included in the analysis?

Yes, authors used multiple imputation for missing values but do not report whether there were follow-up issues in the original study.

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: LOW

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: UNCLEAR

CONCLUSION

Could the patient flow have introduced bias?

RISK: UNCLEAR

Geersing, 2014

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Yes, but for D-dimer testing both a qualitative and quantitative assay was used. With a mix of thresholds for the quantitative assays (the threshold used within the study)

Is the reference standard likely to correctly classify the target condition?

Yes, although CUS is less able to identify recurrent events, notably ipsilateral ones.

Were the reference standard results interpreted without knowledge of the results of the index test?

No, in some studies DVT assessors were not blinded.

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

No part of the reference standard was clinical follow-up but not all patients underwent imaging procedures.

Were all patients included in the analysis?

Yes, authors used multiple imputation for missing values but do not report whether there were follow-up issues in the original study.

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: HIGH

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: HIGH

CONCLUSION

Could the patient flow have introduced bias?

RISK: UNCLEAR

Parpia, 2019

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

No, excluded patients with Wells score >2 which can result in higher NPV (critical outcome).

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Yes

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

No, in some studies DVT assessors were not blinded.

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

No part of the reference standard was clinical follow-up but not all patients underwent imaging procedures.

Were all patients included in the analysis?

Unclear, authors do not report whether there were follow-up issues and did not use imputation.

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: HIGH

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: LOW

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: HIGH

CONCLUSION

Could the patient flow have introduced bias?

RISK: UNCLEAR

Table of excluded studies

Reference	Reason for exclusion
van der Hulle, T., van Es, N., den Exter, P. L., van Es, J., Mos, I. C. M., Douma, R. A., Kruip, M. J. H. A., Hovens, M. M. C., Ten Wolde, M., Nijkeuter, M., Ten Cate, H., Kamphuisen, P. W., Büller, H. R., Huisman, M. V., & Klok, F. A. (2017). Is a normal computed tomography pulmonary angiography safe to rule out acute pulmonary embolism in patients with a likely clinical probability? A patient-level meta-analysis. Thrombosis and haemostasis, 117(8), 1622–1629. https://doi.org/10.1160/TH17-02-0076	Older patient-level meta-analysis than Geersing 2022 and Stals 2022
Kearon, C., de Wit, K., Parpia, S., Schulman, S., Afilalo, M., Hirsch, A., Spencer, F. A., Sharma, S., D'Aragon, F., Deshaies, J. F., Le Gal, G., Lazo-Langner, A., Wu, C., Rudd-Scott, L., Bates, S. M., Julian, J. A., & PEGeD Study Investigators (2019). Diagnosis of Pulmonary Embolism with d-Dimer Adjusted to Clinical Probability. The New England journal of medicine, 381(22), 2125–2134. https://doi.org/10.1056/NEJMoa1909159	Study included in Geersing 2022 and Stals 2022
Mos, I. C., Douma, R. A., Erkens, P. M., Kruip, M. J., Hovens, M. M., van Houten, A. A., Hofstee, H. M., Kooiman, J., Klok, F. A., Büller, H. R., Kamphuisen, P. W., Huisman, M. V., & Prometheus Study Group (2014). Diagnostic outcome management study in patients with clinically suspected recurrent acute pulmonary embolism with a structured algorithm. Thrombosis research, 133(6), 1039–1044. https://doi.org/10.1016/j.thromres.2014.03.050	Study included in Geersing 2022 and Stals 2022
van der Hulle, T., Cheung, W. Y., Kooij, S., Beenen, L. F. M., van Bemmel, T., van Es, J., Faber, L. M., Hazelaar, G. M., Heringhaus, C., Hofstee, H., Hovens, M. M. C., Kaasjager, K. A. H., van Klink, R. C. J., Kruip, M. J. H. A., Loeffen, R. F., Mairuhu, A. T. A., Middeldorp, S., Nijkeuter, M., van der Pol, L. M., Schol-Gelok, S., … YEARS study group (2017). Simplified diagnostic management of suspected pulmonary embolism (the YEARS study): a prospective, multicentre, cohort study. Lancet (London, England), 390(10091), 289–297. https://doi.org/10.1016/S0140-6736(17)30885-1	Study included in Geersing 2022 and Stals 2022
Fabiá Valls, M. J., van der Hulle, T., den Exter, P. L., Mos, I. C., Huisman, M. V., & Klok, F. A. (2015). Performance of a diagnostic algorithm based on a prediction rule, D-dimer and CT-scan for pulmonary embolism in patients with previous venous thromboembolism. A systematic review and meta-analysis. Thrombosis and haemostasis, 113(2), 406–413. https://doi.org/10.1160/TH14-06-0488	Older systematic review than Geersing 2022 and Stals 2022
Bhatt, M., Braun, C., Patel, P., Patel, P., Begum, H., Wiercioch, W., Varghese, J., Wooldridge, D., Alturkmani, H. J., Thomas, M., Baig, M., Bahaj, W., Khatib, R., Kehar, R., Ponnapureddy, R., Sethi, A., Mustafa, A., Nieuwlaat, R., Lim, W., Bates, S. M., … Mustafa, R. A. (2020). Diagnosis of deep vein thrombosis of the lower extremity: a systematic review and meta-analysis of test accuracy. Blood advances, 4(7), 1250–1264. https://doi.org/10.1182/bloodadvances.2019000960	wrong I&C (reports on relevant outcomes for d-dimer standalone without incorporating clinical decision rules)
van der Pol, L. M., Tromeur, C., Bistervels, I. M., Ni Ainle, F., van Bemmel, T., Bertoletti, L., Couturaud, F., van Dooren, Y. P. A., Elias, A., Faber, L. M., Hofstee, H. M. A., van der Hulle, T., Kruip, M. J. H. A., Maignan, M., Mairuhu, A. T. A., Middeldorp, S., Nijkeuter, M., Roy, P. M., Sanchez, O., Schmidt, J., … Artemis Study Investigators (2019). Pregnancy-Adapted YEARS Algorithm for Diagnosis of Suspected Pulmonary Embolism. The New England journal of medicine, 380(12), 1139–1149. https://doi.org/10.1056/NEJMoa1813865	Wrong population (pregnant women)
Righini, M., Van Es, J., Den Exter, P. L., Roy, P. M., Verschuren, F., Ghuysen, A., Rutschmann, O. T., Sanchez, O., Jaffrelot, M., Trinh-Duc, A., Le Gall, C., Moustafa, F., Principe, A., Van Houten, A. A., Ten Wolde, M., Douma, R. A., Hazelaar, G., Erkens, P. M., Van Kralingen, K. W., Grootenboers, M. J., … Le Gal, G. (2014). Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA, 311(11), 1117–1124. https://doi.org/10.1001/jama.2014.2135	Study included in Geersing 2022 and Stals 2022
Righini, M., Robert-Ebadi, H., Elias, A., Sanchez, O., Le Moigne, E., Schmidt, J., Le Gall, C., Cornuz, J., Aujesky, D., Roy, P. M., Chauleur, C., Rutschmann, O. T., Poletti, P. A., Le Gal, G., & CT-PE-Pregnancy Group (2018). Diagnosis of Pulmonary Embolism During Pregnancy: A Multicenter Prospective Management Outcome Study. Annals of internal medicine, 169(11), 766–773. https://doi.org/10.7326/M18-1670	Wrong population (pregnant women)
Lim, W., Le Gal, G., Bates, S. M., Righini, M., Haramati, L. B., Lang, E., Kline, J. A., Chasteen, S., Snyder, M., Patel, P., Bhatt, M., Patel, P., Braun, C., Begum, H., Wiercioch, W., Schünemann, H. J., & Mustafa, R. A. (2018). American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism. Blood advances, 2(22), 3226–3256. https://doi.org/10.1182/bloodadvances.2018024828	Wrong design (no information to calculate outcome measures)
Geersing, G. J., Erkens, P. M., Lucassen, W. A., Büller, H. R., Cate, H. T., Hoes, A. W., Moons, K. G., Prins, M. H., Oudega, R., van Weert, H. C., & Stoffers, H. E. (2012). Safe exclusion of pulmonary embolism using the Wells rule and qualitative D-dimer testing in primary care: prospective cohort study. BMJ (Clinical research ed.), 345, e6564. https://doi.org/10.1136/bmj.e6564	Wrong setting (primary care)
Gibson, N. S., Schellong, S. M., Kheir, D. Y., Beyer-Westendorf, J., Gallus, A. S., McRae, S., Schutgens, R. E., Piovella, F., Gerdes, V. E., & Buller, H. R. (2009). Safety and sensitivity of two ultrasound strategies in patients with clinically suspected deep venous thrombosis: a prospective management study. Journal of thrombosis and haemostasis : JTH, 7(12), 2035–2041. https://doi.org/10.1111/j.1538-7836.2009.03635.x	Wrong design (set up to compare different ultrasound strategies, thus different references)
Kleinjan, A., Di Nisio, M., Beyer-Westendorf, J., Camporese, G., Cosmi, B., Ghirarduzzi, A., Kamphuisen, P. W., Otten, H. M., Porreca, E., Aggarwal, A., Brodmann, M., Guglielmi, M. D., Iotti, M., Kaasjager, K., Kamvissi, V., Lerede, T., Marschang, P., Meijer, K., Palareti, G., Rickles, F. R., … Büller, H. R. (2014). Safety and feasibility of a diagnostic algorithm combining clinical probability, d-dimer testing, and ultrasonography for suspected upper extremity deep venous thrombosis: a prospective management study. Annals of internal medicine, 160(7), 451–457. https://doi.org/10.7326/M13-2056	Wrong design (set up to compare different ultrasound strategies, thus different references)
Takada, T., van Doorn, S., Parpia, S., de Wit, K., Anderson, D. R., Stevens, S. M., Woller, S. C., Ten Cate-Hoek, A. J., Elf, J. L., Kraaijenhagen, R. A., Schutgens, R. E. G., Wells, P. S., Kearon, C., Moons, K. G. M., & Geersing, G. J. (2020). Diagnosing deep vein thrombosis in cancer patients with suspected symptoms: An individual participant data meta-analysis. Journal of thrombosis and haemostasis : JTH, 18(9), 2245–2252. https://doi.org/10.1111/jth.14900	Wrong design (set-up to explore reasons for reduced diagnostic accuracy in cancer patients suspected of DVT); All underlying studies included in IPD analyses Geersing 2014
van Es, N., van der Hulle, T., van Es, J., den Exter, P. L., Douma, R. A., Goekoop, R. J., Mos, I. C., Galipienzo, J., Kamphuisen, P. W., Huisman, M. V., Klok, F. A., Büller, H. R., & Bossuyt, P. M. (2016). Wells Rule and d-Dimer Testing to Rule Out Pulmonary Embolism: A Systematic Review and Individual-Patient Data Meta-analysis. Annals of internal medicine, 165(4), 253–261. https://doi.org/10.7326/M16-0031	Older systematic review and IPD meta-analysis than Geersing 2022 and Stals 2022
Revel, M. P., Sanchez, O., Couchon, S., Planquette, B., Hernigou, A., Niarra, R., Meyer, G., & Chatellier, G. (2012). Diagnostic accuracy of magnetic resonance imaging for an acute pulmonary embolism: results of the 'IRM-EP' study. Journal of thrombosis and haemostasis : JTH, 10(5), 743–750. https://doi.org/10.1111/j.1538-7836.2012.04652.x	Wrong comparator (only patients positive outcome on clinical probability and D-dimer testing); wrong design (set up to evaluate usage MRI in diagnosing pulmonary embolism)
Elf, J. L., Strandberg, K., Nilsson, C., & Svensson, P. J. (2009). Clinical probability assessment and D-dimer determination in patients with suspected deep vein thrombosis, a prospective multicenter management study. Thrombosis research, 123(4), 612–616. https://doi.org/10.1016/j.thromres.2008.04.007	Included in IPD analyses Geersing 2014 and Parpia 2020
Engelberger, R. P., Aujesky, D., Calanca, L., Staeger, P., Hugli, O., & Mazzolai, L. (2011). Comparison of the diagnostic performance of the original and modified Wells score in inpatients and outpatients with suspected deep vein thrombosis. Thrombosis research, 127(6), 535–539. https://doi.org/10.1016/j.thromres.2011.02.008	Wrong design (compare original and modified Wells score, not enough information to calculate diagnostic accuracy information for Wells score + d-dimer)
Hendriksen, J. M., Lucassen, W. A., Erkens, P. M., Stoffers, H. E., van Weert, H. C., Büller, H. R., Hoes, A. W., Moons, K. G., & Geersing, G. J. (2016). Ruling Out Pulmonary Embolism in Primary Care: Comparison of the Diagnostic Performance of "Gestalt" and the Wells Rule. Annals of family medicine, 14(3), 227–234. https://doi.org/10.1370/afm.1930	Wrong setting (primary care)
Di Nisio, M., Van Sluis, G. L., Bossuyt, P. M., Büller, H. R., Porreca, E., & Rutjes, A. W. (2010). Accuracy of diagnostic tests for clinically suspected upper extremity deep vein thrombosis: a systematic review. Journal of thrombosis and haemostasis : JTH, 8(4), 684–692. https://doi.org/10.1111/j.1538-7836.2010.03771.x	Wrong design (comparing different diagnostic test, no information combination clinical decision rules + d-dimer)
Huisman, M. V., & Klok, F. A. (2013). Diagnostic management of acute deep vein thrombosis and pulmonary embolism. Journal of thrombosis and haemostasis : JTH, 11(3), 412–422. https://doi.org/10.1111/jth.12124	Wrong publication (narrative review)
Lucassen, W. A., Douma, R. A., Toll, D. B., Büller, H. R., & van Weert, H. C. (2010). Excluding pulmonary embolism in primary care using the Wells-rule in combination with a point-of care D-dimer test: a scenario analysis. BMC family practice, 11, 64. https://doi.org/10.1186/1471-2296-11-64	Wrong setting (primary care)
Linkins, L. A., Bates, S. M., Lang, E., Kahn, S. R., Douketis, J. D., Julian, J., Parpia, S., Gross, P., Weitz, J. I., Spencer, F. A., Lee, A. Y., O'Donnell, M. J., Crowther, M. A., Chan, H. H., Lim, W., Schulman, S., Ginsberg, J. S., & Kearon, C. (2013). Selective D-dimer testing for diagnosis of a first suspected episode of deep venous thrombosis: a randomized trial. Annals of internal medicine, 158(2), 93–100. https://doi.org/10.7326/0003-4819-158-2-201301150-00003	Included in Parpia 2019
Robert-Ebadi, H., Mostaguir, K., Hovens, M. M., Kare, M., Verschuren, F., Girard, P., Huisman, M. V., Moustafa, F., Kamphuisen, P. W., Buller, H. R., Righini, M., & Le Gal, G. (2017). Assessing clinical probability of pulmonary embolism: prospective validation of the simplified Geneva score. Journal of thrombosis and haemostasis : JTH, 15(9), 1764–1769. https://doi.org/10.1111/jth.13770	Subgroup analysis in same cohort as Righini 2014
de Wit, K., Al-Haimus, F., Hu, Y., Ikesaka, R., Chan, N., Ibrahim, Q., Klyn, J., Clayton, N., & Germini, F. (2022). Comparison of YEARS and Adjust-Unlikely D-dimer Testing for Pulmonary Embolism in the Emergency Department. Annals of emergency medicine, S0196-0644(22)01118-0. Advance online publication. https://doi.org/10.1016/j.annemergmed.2022.09.014	Wrong reference (30 days instead of 3 months follow up for pulmonary embolism diagnosis)
Riva, N., Camporese, G., Iotti, M., Bucherini, E., Righini, M., Kamphuisen, P. W., Verhamme, P., Douketis, J. D., Tonello, C., Prandoni, P., Ageno, W., & PALLADIO Study Investigators (2018). Age-adjusted D-dimer to rule out deep vein thrombosis: findings from the PALLADIO algorithm. Journal of thrombosis and haemostasis : JTH, 16(2), 271–278. https://doi.org/10.1111/jth.13905	Wrong design (set up to compare different ultrasound strategies after D-dimer testing, thus different references)

Verantwoording

Beoordelingsdatum en geldigheid

Laatst beoordeeld : 23-09-2025

Initiatief en autorisatie

Initiatief:

Nederlandse Internisten Vereniging

Geautoriseerd door:

Nederlands Huisartsen Genootschap
Nederlandse Internisten Vereniging
Nederlandse Orthopaedische Vereniging
Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose
Nederlandse Vereniging van Maag-Darm-Leverartsen
Nederlandse Vereniging voor Anesthesiologie
Nederlandse Vereniging voor Cardiologie
Nederlandse Vereniging voor Dermatologie en Venereologie
Nederlandse Vereniging voor Heelkunde
Nederlandse Vereniging voor Kindergeneeskunde
Nederlandse Vereniging voor Klinische Geriatrie
Nederlandse Vereniging voor Neurologie
Nederlandse Vereniging voor Thoraxchirurgie
Nederlandse Vereniging van Ziekenhuisapothekers
Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie
Nederlandse Vereniging voor Klinische Chemie en Laboratoriumgeneeskunde
Nederlandse Vereniging voor Intensive Care
Nederlandse Vereniging voor Mond- Kaak- en Aangezichtschirurgie
Harteraad

Algemene gegevens

Voor meer details over de gebruikte richtlijnmethodologie verwijzen wij u naar de Werkwijze. Relevante informatie voor de ontwikkeling/herziening van deze richtlijnmodule is hieronder weergegeven.

De ontwikkeling/herziening van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten (www.demedischspecialist.nl/kennisinstituut) en werd gefinancierd uit de Stichting Kwaliteitsgelden Medisch Specialisten (SKMS). Patiëntenparticipatie bij deze richtlijn werd medegefinancierd uit de Kwaliteitsgelden Patiënten Consumenten (SKPC) binnen het programma KIDZ. De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.

Samenstelling werkgroep

Voor het ontwikkelen van de richtlijnmodule is in 2021 een multidisciplinaire werkgroep ingesteld, bestaande uit vertegenwoordigers van alle relevante specialismen (zie hiervoor de Samenstelling van de werkgroep) die betrokken zijn bij de zorg voor patiënten die antitrombotische therapie dan wel tromboseprofylaxe gebruiken.

Kerngroep

Prof. dr. M.V. (Menno) Huisman, internist-vasculaire geneeskunde, LUMC, NIV (voorzitter)
Dr. M.J.H.A. (Marieke) Kruip, internist-hematoloog, Erasmus MC, NIV, NVVH (Nederlandse Vereniging voor Hematologie)
Prof. Dr. F.A. (Erik) Klok, internist-vasculaire geneeskunde, LUMC, NIV
Dr. J. (Jenneke) Leentjens, internist-vasculaire geneeskunde, RadboudUMC, NIV (vanaf 2023)
Dr. N. (Nick) van Es, internist-vasculaire geneeskunde, Amsterdam UMC, NIV (vanaf 2023)
Dr. M.A. (Marc) Brouwer, cardioloog, RadboudUMC, NVVC
Dr. H.B. (Harmen) Ettema, orthopedisch chirurg, Isala, NOV
Dr. B. (Banne) Nemeth, aios orthopedie, LUMC, NOV
Dr. A.M. (Arno) Wiersema, vaatchirurg, Dijklander Ziekenhuis, NVVH (tot 2023)
Dr. M.C. (Michiel) Warlé, vaatchirurg, RadboudUMC, NVVH (vanaf 2024)
Dr. M.E. (Maarten) Tushuizen, maag-darm-leverarts, LUMC, NVMDL
Dr. J.M. (Jonathan) Coutinho, neuroloog, Amsterdam UMC, NVN
Drs. M.H. (Monique) Suijker, kinderarts-hematoloog, UMC Utrecht, NVK
Drs. P (Paul) Smits, huisarts/ Kaderhuisarts HVZ, NHG

Klankbordgroep

Dr. J.J.C.M. (Sjef) van de Leur, arts klinische chemie, Isala, NVKC
Dr. M.G. (Mariëlle) van Pampus, gynaecoloog, OLVG, NVOG
Drs. R.J. (Rutger) Lely, radioloog, Amsterdam UMC, NVVR
Dr. C. (Bibi) van Montfrans, dermatoloog, Erasmus MC, NVDV
Dr. R.A. (Richard) Faaij, klinisch geriater, Diakonessenhuis, NVKG
Dr. B. (Baucke) van Minnen, kaakchirurg, UMCG, NVMKA
Drs. N. (Noa) Rosenberg, beleidsadviseur, Harteraad (vanaf mei 2024)
I.G.J. (Ilse) Verstraaten MSc, beleidsadviseur, Harteraad (tot 2024)
Dr. N. (Nakisa) Khorsand, ziekenhuisapotheker, OLVG, NVZA
Dr. M.F. (Margreet) van Herwaarden, openbaar apotheker, KNMP
Dr. E.T.T.L. (Eric) Tjwa, MDL-arts, RadboudUMC, NVMDL
Dr. L.M. (Linda) de Heer, cardio-thoracaal chirurg, UMC Utrecht, NVT
Prof. dr. S. (Saskia) Middeldorp, internist-vasculaire geneeskunde, Radboudumc, NIV
Dr. J.M.M.B. (Hans-Martin) Otten, internist-oncoloog, Meander MC, NIV
Dr. E.J. (Esther) Nossent, longarts, Amsterdam UMC, NVALT
Dr. C.H. (Heleen) van Ommen, kinderarts-hematoloog, Erasmus MC, NVK
Dr. K.M.J. (Katja) Heitink, kinderarts-oncoloog, Prinses Maxima Centrum, NVK
Prof. dr. N.P. (Nicole) Juffermans, intensivist, Amsterdam UMC, NVIC
Dr. M.C.A. (Marcella) Muller, intensivist, Amsterdam UMC, NVIC

Met ondersteuning van

H. (Hanneke) Olthuis, adviseur, Kennisinstituut van de Federatie Medisch Specialisten
H.J. (Harm-Jan) van der Hart, adviseur, Kennisinstituut van de Federatie Medisch Specialisten

Belangenverklaringen

Een overzicht van de belangen van werkgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten via secretariaat@kennisinstituut.nl.

Werkgroeplid	Functie	Nevenfuncties	Gemelde belangen	Ondernomen actie
Huisman (voorzitter)	Internist vasculaire geneeskunde	voorzitter Dutch Thrombosis Network – onbetaald voorzitter Nationaal Kennisplatform Antistollingszorg – onbetaald medisch leider Trombosedienst Leiden - detachering LUMC	ZonMW Dutch Healthcare Fund – herseninfarct na covid-19 en register van patienten met atrium fibrilleren NHS – herseninfarct na covid-19 Boehringer Ingelheim – register atriumfibrilleren – afgesloten Bristol-Myers Squibb/Pfizer – VTE behandeling bij patienten met maligniteit – afgesloten Bayer Health Care - VTE behandeling bij patienten met maligniteit – afgesloten Aspen – webinar anti-Xa bepaling bij LMWH – afgesloten Daiichi-Sankyo – deelname studie cancer associated thrombosis – afgesloten à op geen van deze projecten projectleider, betreft unrestricted grants en veelal financiering promotietrajecten.	Geen restricties
Banne Nemeth	Orthopedisch chirurg in opleiding	Postdoc klinische epidemiologie en orthopedie, LUMC	Trombosestichting - “VTE following total hip and knee arthroplasty: prediction is the future“	Geen restricties
Harmen Ettema	Orthopedisch chirurg Isala zwolle	Geen	Gemeld bij herbevestiging in 2025: ZonMW, Distinct trial, tromboseprofylaxe bij orthopedische ingrepen, geen projectleider	Geen restricties
Jonathan Coutinho	neuroloog Amsterdam UMC	Geen	Bayer - Pacific stroke en Oceanic stroke study, onderzoek naar inzet van nieuw middel bij patienten met een beroerte, national leader en SC member) Boehringer Ingelheim - RESPECT CVT, vergelijking dabigatran Etexilate met Warfarin, SC member, AstraZeneca, Portola - ANNEXA-I studie, onderzoek naar inzet van Andexanet alfa bij patienten met intracraniele bloeding, national leader Gemeld bij herbevestiging in 2025: ZonMw, Hartstichting, Eurostars, Trombosestichting, Europese Unie, Health-Holland, NWO, onderzoek naar diagnostiek en behandeling van een beroerte Co-founder TrianecT BV fellow European Stroke Organization lid richtlijn commissie ESO over cerebrale sinustrombose editorial board member Stroke en Journal of Neurology leadership International cerebral venous thrombosis consortium	Restricties t.a.v. besluitvorming modules over andexanet alfa bij bloedingen geen restricties ten gevolge van rol pacific stroke study en dabigatran etixilate/warfarin bij CVT, aangezien deze patientengroepen geen onderwerp zijn van deze richtlijnherziening.
Klok	Internist vasculaire geneeskunde LUMC Leiden	Bestuur NVIVG Bestuur ESC werkgroep pulmonale circulatie Bestuur ISTH SSC werkgroep diagnostische en predictieve variabelen (tot 2024) Bestuur Dutch Thrombosis Network Gastwetenschapper Universiteit Mainz (Duitsland) Gemeld bij herbevestiging in 2024: Medisch leider Trombosedienst Leiden (tot 1-1-25)	Bayer, Leo Pharma en BSCI – voorzitter van een internationale werkgroep om een standaard set van uitkomsten (ICHOM) te maken voor VTE – inmiddels afgesloten Actelion en The Netherlands Organisation for Health Research and Development - mede-aanvrager van 3 ZonMw beurzen voor onderzoek naar voorkomen van VTE en herseninfarcten bij COVID-19 patiënten (DC&TC en CORONIS consortium - DC&TC wordt ook ondersteund door TSN en een unrestricted grant van Actelion voor diagnostiek deel - afgesloten The Dutch Thrombosis Association -onderzoek naar nieuwe beeldvormende technieken van trombose The Dutch Heart Foundation - lange termijn prognose van longembolie - afgesloten the Horizon Europe Program - voorzitter van een Europees consortium dat tot doel heeft het gebruik van antitrombotische medicatie in de laatste levensfase te optimaliseren	Geen restricties
Kruip	Hematoloog Gemeld bij herbevestiging in 2024: Directeur Kwaliteit & Patientenzorg, Erasmus MC, betaald	Medisch leider trombosedienst Star-shl (0.2FTE), gedetacheerd vanuit Erasmus MC, betaald voorzitter Federatie Nederlandse Trombosediensten (FNT), onbetaald Gemeld bij herbevestiging in 2024: RvC Lenticure, onbetaald RvT Trombosestichting, onbetaald	Horizon Europe programme Trombosestichting/ZonMw Sprekers vergoedingen gehad van Sobi, Roche en Bristol Myers Squibb; betaling aan het Erasmus MC	Geen restricties
Maarten Tushuizen	MDL-arts LUMC	Geen	Maag-Lever-Darmstichting (MLDS)	Geen restricties
Marc Brouwer	Cardioloog Radboudumc	Geen	Nee	Geen restricties
Paul Smits	huisarts, zelfstandig	Coördinator onderwijscommissie harvaatHAG	geen	Geen restricties
Monique Suijker	Kinderarts-hematoloog werkzaam bij Van Creveldkliniek, UMCU	Geen	Geen lopende studies Bayer en Janssen - Einstein Jr studie - gebruik Rivaroxaban bij kinderen – afgesloten	Geen restricties
Arno Wiersema (teruggetrokken, tot 2024)	Vaatchirurg, Dijklander ziekenhuis	Geen	ZonMw, Amsterdam UMC, Dijklander zh en Medtronic - www.action-1.nl - betreft onderzoek naar rol van heparine bij een open buikslagader operatie, rol als projectleider	Restricties ten aanzien van besluitvorming over heparine.
Michiel Warlé (vanaf 2024)	Vaatchirurg Radboudumc	Werkgroep Landelijk Kennisplatform Antistolling	ZEGG/ZonMw- GENPAD studie (Cyp2c19 genotypering bij Clopidogrel en perifeer arterieel vaatlijden – hoofdonderzoeker Gemeld bij herbevestiging in 2025: NWO-OTP, Wireless clot retriever, projectleider	Geen restricties
Nick van Es (vanaf 2023)	Internist-vasculaire geneeskunde, Amsterdam UMC, locatie AMC	Geen	Trombosestichting – PREVENT (PREdicting VENous Thromboembolism in pancreatic cancer patients) NWO - Blood vessels-on-chip to understand and target COVID-19 intravascular coagulation Gemeld bij herbevestiging in 2024: Deelname Podcast LEO Pharma (2024) Sprekersvergoeding Werfen en Amgen (2024) Eenmalige adviesraad Pfizer (2019) Anthos Therapeutics, ASTER-study en MAGNOLIA-study, effectiviteit en veiligheid van abelacimab (niet geregistreerd middel) in patienten met kankergerelateerde trombose, rol als national lead investigator. NWO, Atherosclerotic cardiovascular disease induced by immune checkpoint inhibitors, rol als projecteleider	Geen restricties
Leentjens (vanaf 2023)	Internist-vasculair geneeskundige, Radboudumc	Geen	Astra Zeneca - scientific steering comité van database studie over bloedingen bij ptn die Xa remmers gebruiken (apixaban, edoxaban Adviesraad Viatris (tot begin 2024) Synapse B.V. – studie naar interactie tussen hemostase en inflammatie bij patiënten met een herseninfarct op jonge leeftijd	Geen restricties
Actieve klankbordgroepleden
Esther Nossent	Longarts Amsterdam UMC	Geen	Janssen, Bayer, MSD, United Therapeutics, Ferrer - OPTICS Boehringer Ingelheim B.V., AbbVie, PEXAS – P402 ILD-extension Gemeld bij herbevestiging in 2025: Deelnemer ICHOM-project, internationale werkgroep om een standaardset van uitkomsten te maken voor VTE Sprekersvergoedingen voor onderwijsevents in afgelopen 5 jaar: Astra Zeneca, Janssen, Bayer/ MSD, Boehringer Ingelheim B.V., Chiesi, GlaxoSmithKline B.V., Novartis, Roche, United Therapeutics/Ferrer Deelname adviesraden: Bayer/MSD (lopend) en Boehringer Ingelheim (afgesloten)	Geen restricties
Heleen van Ommen	Hoofd afd. Kinderhematologie & kinderoncologie Erasmus MC Sophia Kinderziekenhuis	Geen	Daiicho Sankyo - Fase 3 trial effectiviteit van edoxaban voor behandeling van trombose bij kinderen, local PI en steeringCie - afgesloten Octopharma - Microscopic evaluation of clots in ECMO systems, rol als PI BI/BMS en INVENT – chair IPTN ThromPED registry (international observational registry/study of children with thrombosis, Adviseur voor verschillende farmaceuten voor ontwikkeling van onderzoek van antistollingsmiddelen of antidota bij kinderen zoals Asundexian (Bayer BV), andexanet (Astra Zeneca) – tot deelname clusterstuurgroep	Geen restricties
Eric Tjwa	MDL arts, Radboudumc	Geen	Geen Gemeld bij herbevestiging in 2025: Geen betrokkenheid bij onderzoeken die direct/indirect verband houden met de inhoud van de richtlijn	Geen restricties
Hans-Martin Otten (vanaf 2024)	Internist Meander MC	Lid METC UMCU, betaald	Eenmalig advies aan Leo Pharma: standpunten over de zorg bij patiënten met VTE en kanker in NL (19-11-2019) ANT-007 & ANT-008 multi-center studies, abelcimab vs apixaban bij kankergerelateerde VTE, participatie in Meander MC Hukusai-study, participatie - afgesloten Einstein-study, adjudicatie-cie - afgesloten	Geen restricties
Noa Rosenberg (vanaf 2024)	Beleidsadviseur		Geen	Geen restricties
Katja Heitink – Pollé	Kinderoncoloog Prinses Máxima Centrum	Landelijke werkgroep trombose bij kinderen	geen	Geen restricties

Inbreng patiëntenperspectief

De werkgroep besteedde aandacht aan het patiëntenperspectief door uitnodigen van Stichting Harteraad voor de schriftelijke knelpuntenanalyse en door een patiëntvertegenwoordiger van Stichting Harteraad toe te voegen aan de klankbordgroep. De verkregen input is meegenomen bij het opstellen van de uitgangsvragen, de keuze voor de uitkomstmaten en bij het opstellen van de overwegingen (zie alinea waarden en voorkeuren van patiënten). De conceptrichtlijn is tevens voor commentaar voorgelegd aan Stichting Harteraad en Stichting Kind en Ziekenhuis en de eventueel aangeleverde commentaren zijn bekeken en verwerkt.

Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz

Bij de richtlijnmodule voerde de werkgroep conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uitom te beoordelen of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling is de richtlijnmodule op verschillende domeinen getoetst (zie het stroomschema bij Werkwijze).

Module	Uitkomst raming	Toelichting
Diagnostiek VTE	geen financiële gevolgen	Hoewel uit de toetsing volgt dat de aanbevelingen breed toepasbaar zijn (5.000-40.000 patiënten), volgt ook uit de toetsing dat het overgrote deel (±90%) van de zorgaanbieders en zorgverleners al aan de norm. Er worden daarom geen substantiële financiële gevolgen verwacht.

Zoekverantwoording

Algemene informatie

Richtlijn: NIV antitrombotisch beleid
Uitgangsvraag: UV1, UV2 Wat is de optimale diagnostiek van patiënten met een vermoeden op een VTE?
Database(s): Ovid/Medline, Embase	Datum: 15-12-2022
Periode: 2009-	Talen: nvt
Literatuurspecialist: Ingeborg van Dusseldorp
BMI zoekblokken: voor verschillende opdrachten wordt (deels) gebruik gemaakt van de zoekblokken van BMI-Online https://blocks.bmi-online.nl/ Bij gebruikmaking van een volledig zoekblok zal naar de betreffende link op de website worden verwezen.

Zoekopbrengst

	EMBASE	OVID/MEDLINE	Ontdubbeld
SRs	57	30	64*
RCTs	20	11	24*
Observationele studies	381	131	420*
Overig	268	68	273
Totaal			508*

*in Rayyan

Zoekstrategie

Embase

No.	Query	Results
#28	#9 AND #27 sleutelartikelen gevonden in SR,RCT, OBS	3
#27	#21 OR #22 OR #23	458
#26	#15 NOT #23 NOT #22 NOT #21 Overige diagnostische studies	268
#25	#23 NOT #22 NOT #21 OBS	381
#24	#22 NOT #21 RCT	20
#23	#15 AND (#19 OR #20)	420
#22	#15 AND #18	31
#21	#15 AND #17 SR	57
#20	'case control study'/de OR 'comparative study'/exp OR 'control group'/de OR 'controlled study'/de OR 'controlled clinical trial'/de OR 'crossover procedure'/de OR 'double blind procedure'/de OR 'phase 2 clinical trial'/de OR 'phase 3 clinical trial'/de OR 'phase 4 clinical trial'/de OR 'pretest posttest design'/de OR 'pretest posttest control group design'/de OR 'quasi experimental study'/de OR 'single blind procedure'/de OR 'triple blind procedure'/de OR (((control OR controlled) NEAR/6 trial):ti,ab,kw) OR (((control OR controlled) NEAR/6 (study OR studies)):ti,ab,kw) OR (((control OR controlled) NEAR/1 active):ti,ab,kw) OR 'open label':ti,ab,kw OR (((double OR two OR three OR multi OR trial) NEAR/1 (arm OR arms)):ti,ab,kw) OR ((allocat NEAR/10 (arm OR arms)):ti,ab,kw) OR placebo:ti,ab,kw OR 'sham-control':ti,ab,kw OR (((single OR double OR triple OR assessor) NEAR/1 (blind* OR masked)):ti,ab,kw) OR nonrandom:ti,ab,kw OR 'non-random':ti,ab,kw OR 'quasi-experiment':ti,ab,kw OR crossover:ti,ab,kw OR 'cross over':ti,ab,kw OR 'parallel group':ti,ab,kw OR 'factorial trial':ti,ab,kw OR ((phase NEAR/5 (study OR trial)):ti,ab,kw) OR ((case* NEAR/6 (matched OR control)):ti,ab,kw) OR ((match NEAR/6 (pair OR pairs OR cohort* OR control* OR group* OR healthy OR age OR sex OR gender OR patient* OR subject* OR participant)):ti,ab,kw) OR ((propensity NEAR/6 (scor OR match)):ti,ab,kw) OR versus:ti OR vs:ti OR compar:ti OR ((compar* NEAR/1 study):ti,ab,kw) OR (('major clinical study'/de OR 'clinical study'/de OR 'cohort analysis'/de OR 'observational study'/de OR 'cross-sectional study'/de OR 'multicenter study'/de OR 'correlational study'/de OR 'follow up'/de OR cohort:ti,ab,kw OR 'follow up':ti,ab,kw OR followup:ti,ab,kw OR longitudinal:ti,ab,kw OR prospective:ti,ab,kw OR retrospective:ti,ab,kw OR observational:ti,ab,kw OR 'cross sectional':ti,ab,kw OR cross?ectional:ti,ab,kw OR multicent:ti,ab,kw OR 'multi-cent':ti,ab,kw OR consecutive:ti,ab,kw) AND (group:ti,ab,kw OR groups:ti,ab,kw OR subgroup:ti,ab,kw OR versus:ti,ab,kw OR vs:ti,ab,kw OR compar:ti,ab,kw OR 'odds ratio':ab OR 'relative odds':ab OR 'risk ratio':ab OR 'relative risk*':ab OR 'rate ratio':ab OR aor:ab OR arr:ab OR rrr:ab OR ((('or' OR 'rr') NEAR/6 ci):ab)))	13681486
#19	'major clinical study'/de OR 'clinical study'/de OR 'case control study'/de OR 'family study'/de OR 'longitudinal study'/de OR 'retrospective study'/de OR 'prospective study'/de OR 'comparative study'/de OR 'cohort analysis'/de OR ((cohort NEAR/1 (study OR studies)):ab,ti) OR (('case control' NEAR/1 (study OR studies)):ab,ti) OR (('follow up' NEAR/1 (study OR studies)):ab,ti) OR (observational NEAR/1 (study OR studies)) OR ((epidemiologic NEAR/1 (study OR studies)):ab,ti) OR (('cross sectional' NEAR/1 (study OR studies)):ab,ti)	6767914
#18	'randomized controlled trial'/exp OR random:ti,ab OR (((pragmatic OR practical) NEAR/1 'clinical trial'):ti,ab) OR ((('non inferiority' OR noninferiority OR superiority OR equivalence) NEAR/3 trial*):ti,ab) OR rct:ti,ab,kw	1839814
#17	'meta analysis'/exp OR 'meta analysis (topic)'/exp OR metaanaly:ti,ab OR 'meta analy':ti,ab OR metanaly:ti,ab OR 'systematic review'/de OR 'cochrane database of systematic reviews'/jt OR prisma:ti,ab OR prospero:ti,ab OR (((systemati OR scoping OR umbrella OR 'structured literature') NEAR/3 (review* OR overview)):ti,ab) OR ((systemic NEAR/1 review):ti,ab) OR (((systemati OR literature OR database* OR 'data base') NEAR/10 search):ti,ab) OR (((structured OR comprehensive* OR systemic) NEAR/3 search):ti,ab) OR (((literature NEAR/3 review):ti,ab) AND (search:ti,ab OR database:ti,ab OR 'data base':ti,ab)) OR (('data extraction':ti,ab OR 'data source':ti,ab) AND 'study selection':ti,ab) OR ('search strategy':ti,ab AND 'selection criteria':ti,ab) OR ('data source':ti,ab AND 'data synthesis':ti,ab) OR medline:ab OR pubmed:ab OR embase:ab OR cochrane:ab OR (((critical OR rapid) NEAR/2 (review* OR overview* OR synthes)):ti) OR ((((critical OR rapid) NEAR/3 (review OR overview* OR synthes)):ab) AND (search:ab OR database:ab OR 'data base':ab)) OR metasynthes:ti,ab OR 'meta synthes':ti,ab	733409
#16	#9 AND #15	3
#15	#11 AND #12	725
#14	#9 NOT #13	2
#13	#9 AND #11	3
#12	'sensitivity and specificity'/de OR sensitiv:ab,ti OR specific:ab,ti OR predict*:ab,ti OR 'roc curve':ab,ti OR 'receiver operator':ab,ti OR 'receiver operators':ab,ti OR likelihood:ab,ti OR 'diagnostic error'/exp OR 'diagnostic accuracy'/exp OR 'diagnostic test accuracy study'/exp OR 'inter observer':ab,ti OR 'intra observer':ab,ti OR interobserver:ab,ti OR intraobserver:ab,ti OR validity:ab,ti OR kappa:ab,ti OR reliability:ab,ti OR reproducibility:ab,ti OR ((test NEAR/2 're-test'):ab,ti) OR ((test NEAR/2 'retest'):ab,ti) OR 'reproducibility'/exp OR accuracy:ab,ti OR 'differential diagnosis'/exp OR 'validation study'/de OR 'measurement precision'/exp OR 'diagnostic value'/exp OR 'reliability'/exp OR 'predictive value'/exp OR ppv:ti,ab,kw OR npv:ti,ab,kw	9522259
#11	#10 AND [1-1-2009]/sd NOT ('conference abstract'/it OR 'editorial'/it OR 'letter'/it OR 'note'/it) NOT (('animal'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'nonhuman'/exp) NOT 'human'/exp)	1448
#10	#5 NOT (('adolescent'/exp OR 'child'/exp OR adolescent:ti,ab,kw OR child:ti,ab,kw OR schoolchild:ti,ab,kw OR infant:ti,ab,kw OR girl:ti,ab,kw OR boy:ti,ab,kw OR teen:ti,ab,kw OR teens:ti,ab,kw OR teenager:ti,ab,kw OR youth:ti,ab,kw OR pediatr:ti,ab,kw OR paediatr:ti,ab,kw OR puber:ti,ab,kw) NOT ('adult'/exp OR 'aged'/exp OR 'middle aged'/exp OR adult:ti,ab,kw OR man:ti,ab,kw OR men:ti,ab,kw OR woman:ti,ab,kw OR women:ti,ab,kw))	2771
#9	#6 OR #7 OR #8	5
#8	'diagnosis of pulmonary embolism with d-dimer adjusted to clinical probability' NOT guy NOT winger	1
#7	'pregnancy-adapted years algorithm for diagnosis of suspected pulmonary embolism'	2
#6	'simplified diagnostic management of suspected pulmonary embolism (the years study): a prospective, multicentre, cohort study'	2
#5	#2 AND #3 AND #4	2832
#4	'd dimer'/exp OR 'd dimer':ti,ab,kw OR 'crosslinked fibrin degradation product':ti,ab,kw OR 'fibrin degradation product d dimer':ti,ab,kw	41232
#3	'clinical decision rule'/exp OR 'decision making'/exp OR 'diagnostic test'/exp OR ((decision* NEAR/3 (making OR rule)):ti,ab,kw) OR 'clinical pretest probabilit':ti,ab,kw OR 'c ptp':ti,ab,kw	1770358
#2	'venous thromboembolism'/exp OR 'deep vein thrombosis'/exp OR 'lung embolism'/exp OR (((venous OR vein OR lung OR pulmonary) NEAR/3 (embol* OR microembol* OR thromboembol)):ti,ab,kw) OR vte:ti,ab,kw OR dvt:ti,ab,kw OR ((deep NEAR/3 (thromb OR 'blood clot' OR embol)):ti,ab,kw)	234618
#1	'2022 esc guidelines on cardio-oncology developed in collaboration with the european hematology association (eha), the european society for therapeutic radiology and oncology'	2

Ovid/Medline

#	Searches	Results
19	9 not 16 not 15 not 14 overige diagnostische studies	68
18	16 not 15 not 14 OBS	131
17	15 not 14 RCT	11
16	9 and (12 or 13)	156
15	9 and 11	19
14	9 and 10 SR	30
13	Case-control Studies/ or clinical trial, phase ii/ or clinical trial, phase iii/ or clinical trial, phase iv/ or comparative study/ or control groups/ or controlled before-after studies/ or controlled clinical trial/ or double-blind method/ or historically controlled study/ or matched-pair analysis/ or single-blind method/ or (((control or controlled) adj6 (study or studies or trial)) or (compar* adj (study or studies)) or ((control or controlled) adj1 active) or "open label" or ((double or two or three or multi or trial) adj (arm or arms)) or (allocat adj10 (arm or arms)) or placebo* or "sham-control" or ((single or double or triple or assessor) adj1 (blind or masked)) or nonrandom* or "non-random" or "quasi-experiment" or "parallel group" or "factorial trial" or "pretest posttest" or (phase adj5 (study or trial)) or (case adj6 (matched or control)) or (match adj6 (pair or pairs or cohort* or control* or group* or healthy or age or sex or gender or patient* or subject* or participant)) or (propensity adj6 (scor or match))).ti,ab,kf. or (confounding adj6 adjust).ti,ab. or (versus or vs or compar).ti. or ((exp cohort studies/ or epidemiologic studies/ or multicenter study/ or observational study/ or seroepidemiologic studies/ or (cohort or 'follow up' or followup or longitudinal* or prospective* or retrospective* or observational* or multicent* or 'multi-cent' or consecutive).ti,ab,kf.) and ((group or groups or subgroup* or versus or vs or compar).ti,ab,kf. or ('odds ratio' or 'relative odds' or 'risk ratio' or 'relative risk' or aor or arr or rrr).ab. or (("OR" or "RR") adj6 CI).ab.))	5309800
12	Epidemiologic studies/ or case control studies/ or exp cohort studies/ or Controlled Before-After Studies/ or Case control.tw. or cohort.tw. or Cohort analy$.tw. or (Follow up adj (study or studies)).tw. or (observational adj (study or studies)).tw. or Longitudinal.tw. or Retrospective.tw. or prospective.tw. or consecutive*.tw. or Cross sectional.tw. or Cross-sectional studies/ or historically controlled study/ or interrupted time series analysis/ [Onder exp cohort studies vallen ook longitudinale, prospectieve en retrospectieve studies]	4314474
11	exp randomized controlled trial/ or randomized controlled trials as topic/ or random.ti,ab. or rct?.ti,ab. or ((pragmatic or practical) adj "clinical trial").ti,ab,kf. or ((non-inferiority or noninferiority or superiority or equivalence) adj3 trial*).ti,ab,kf.	1569546
10	meta-analysis/ or meta-analysis as topic/ or (metaanaly* or meta-analy* or metanaly).ti,ab,kf. or systematic review/ or cochrane.jw. or (prisma or prospero).ti,ab,kf. or ((systemati or scoping or umbrella or "structured literature") adj3 (review* or overview)).ti,ab,kf. or (systemic adj1 review).ti,ab,kf. or ((systemati or literature or database* or data-base) adj10 search).ti,ab,kf. or ((structured or comprehensive* or systemic) adj3 search).ti,ab,kf. or ((literature adj3 review) and (search or database* or data-base)).ti,ab,kf. or (("data extraction" or "data source") and "study selection").ti,ab,kf. or ("search strategy" and "selection criteria").ti,ab,kf. or ("data source" and "data synthesis").ti,ab,kf. or (medline or pubmed or embase or cochrane).ab. or ((critical or rapid) adj2 (review or overview* or synthes)).ti. or (((critical or rapid) adj3 (review or overview* or synthes)) and (search or database* or data-base)).ab. or (metasynthes or meta-synthes*).ti,ab,kf.	635722
9	7 and 8	240
8	exp "Sensitivity and Specificity"/ or (Sensitiv* or Specific).ti,ab. or (predict or ROC-curve or receiver-operator).ti,ab. or (likelihood or LR).ti,ab. or exp Diagnostic Errors/ or (inter-observer or intra-observer or interobserver or intraobserver or validity or kappa or reliability).ti,ab. or reproducibility.ti,ab. or (test adj2 (re-test or retest)).ti,ab. or "Reproducibility of Results"/ or accuracy.ti,ab. or Diagnosis, Differential/ or Validation Study/	7633306
7	6 not ((exp animals/ or exp models, animal/) not humans/) not (letter/ or comment/ or editorial/)	323
6	limit 5 to yr="2009 -Current"	345
5	4 not ((Adolescent/ or Child/ or Infant/ or adolescen.ti,ab,kf. or child.ti,ab,kf. or schoolchild.ti,ab,kf. or infant.ti,ab,kf. or girl.ti,ab,kf. or boy.ti,ab,kf. or teen.ti,ab,kf. or teens.ti,ab,kf. or teenager.ti,ab,kf. or youth.ti,ab,kf. or pediatr.ti,ab,kf. or paediatr.ti,ab,kf. or puber.ti,ab,kf.) not (Adult/ or adult.ti,ab,kf. or man.ti,ab,kf. or men.ti,ab,kf. or woman.ti,ab,kf. or women.ti,ab,kf.))	433
4	1 and 2 and 3	436
3	Fibrin Fibrinogen Degradation Products/ or d dimer.ti,ab,kf. or crosslinked fibrin degradation product.ti,ab,kf. or fibrin degradation product d dimer.ti,ab,kf.	19200
2	Clinical Decision Rules/ or Decision Support Techniques/ or Decision Making/ or Diagnostic Tests, Routine/ or (decision* adj3 (making or rule)).ti,ab,kf. or 'clinical pretest probabilit'.ti,ab,kf. or 'c ptp'.ti,ab,kf.	291438
1	Venous Thromboembolism/ or exp Venous Thrombosis/ or exp Pulmonary Embolism/ or ((venous or vein or lung or pulmonary) adj3 (embol* or microembol* or thromboembol)).ti,ab,kf. or vte.ti,ab,kf. or dvt.ti,ab,kf. or (deep adj3 (thromb or 'blood clot' or embol)).ti,ab,kf.	146483

Richtlijnendatabase

Antitrombotisch beleid

Antitrombotisch beleid

Diagnostiek VTE

Uitgangsvraag

Aanbeveling

Overwegingen

Onderbouwing

Achtergrond

Conclusies / Summary of Findings

Samenvatting literatuur

Zoeken en selecteren

Referenties

Evidence tabellen

Verantwoording

Beoordelingsdatum en geldigheid

Initiatief en autorisatie

Algemene gegevens

Samenstelling werkgroep

Belangenverklaringen

Inbreng patiëntenperspectief

Module

Zoekverantwoording

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