The Incidence of Pulmonary Thromboembolism in Critically Ill Patients With COVID-19: A Systematic Review, Meta-Analysis and Meta-Regression of Observational Studies

Purpose Coronavirus disease 2019 (COVID-19) infection is known to be associated with a hypercoagulable and prothrombotic state, especially in critically ill patients. Several observational studies have reported the incidence of thromboembolic events such as pulmonary thromboembolism (PTE). We performed a meta-analysis to estimate the weighted average incidence of PTE in critically ill COVID-19 patients who are admitted to the intensive care unit. Methods We searched MEDLINE via PubMed, Embase and Web of Science for relevant studies from 31 December 2019 till 15 Aug 2020 onwards using the search terms “coronavirus”, “COVID-19”, “SARS-CoV-2”, “2019-nCoV”, “thrombus”, “thrombo*”, “embolus” and “emboli*”. We included prospective and retrospective observational studies that reported the incidence of PTE in critically ill COVID-19 patients who required treatment in the intensive care unit. We identi�ed 14 studies after two phases of screening and extracted data related to study characteristics, patient demographics and the incidence of PTE. Risk of bias was assessed by using the ROBINS-I tool. Statistical analysis was performed with R 3.6.3. Results We included 14 studies with a total of 1182 patients in this study. Almost 100% of patients in this meta-analysis received at least prophylactic anticoagulation. The weighted average incidence of PTE was 11.09% (95% CI 7.72% to 15.69%, I 2 = 78%, Cochran’s Q test P < 0.01). We performed univariate and multivariate meta-regression which identi�ed the proportion of males as a signi�cant source of heterogeneity (P = 0.03, 95% CI 0.00 to -0.09) Conclusion This is the only study that had speci�cally reported the weighted average incidence of PTE in critically ill COVID-19 patients using meta-analytic techniques. The weighted average incidence of PTE remains high even after prophylactic anticoagulation. This study is limited by incomplete data from included studies. More studies are needed to determine the optimal anticoagulation strategy in critically ill COVID-19 patients.


Background
Since the declaration of a global pandemic by the World Health Organization on 11 March 2020, more than 25 million people have been diagnosed with coronavirus disease 2019 .Amongst them, over 800,000 people have died.[1] As we gradually understand more about the pathophysiology and clinical manifestations of COVID-19 infection, a few distinct themes have emerged.One of the more apparent themes is the hypercoagulable, prothrombotic state that critically-ill COVID-19 patients have an a nity for.[2] Early studies rst reported autopsy ndings of micro-thrombus within the pulmonary vasculature of deceased COVID-19 patients.[3] At the same time, other studies started reporting about abnormal coagulation parameters and elevated D-dimer levels in critically-ill COVID-19 patients.[4,5] On the frontline, physicians treating critically-ill COVID-19 patients started noticing an increase in thromboembolic events and line thrombosis.[6]Cognizant of the thromboembolic phenomenon associated with COVID-19, several institutions have published observational studies that reported the incidence of thromboembolic events such as pulmonary thromboembolism (PTE).In this study, we aim to quantitatively synthesize available literature by using meta-analysis of proportions to estimate the weighted average incidence of PTE in critically-ill COVID-19 patients that are admitted to the intensive care unit (ICU).

Study protocol
We conducted this systematic review and meta-analysis following the Cochrane Handbook for Systematic Reviews of Interventions and reported it in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.[7,8] We formulated the study protocol for this systematic review and meta-analysis in an apriori fashion and published it in PROSPERO (CRD42020188647).

Search strategy
We formulated the search strategy after discussion and consensus by all authors.The search strategy included various combinations and permutations of the following search terms: "coronavirus", "COVID-19", "SARS-CoV-2", "2019-nCoV, "thrombus", "thrombo*", "embolus" and "emboli*".We identi ed studies by conducting an exhaustive literature search using MEDLINE via PubMed, Embase and Web of Science.We modi ed the search syntax for compatibility as required for each database.We only included studies that were published after 31 December 2019, which corresponds to the date when Chinese o cials rst reported a cluster of patients diagnosed with pneumonia of unknown cause in Wuhan, Hubei Province to the World Health Organization.[9] We did not restrict language for the search.After eligible full-text studies were identi ed, we performed manual backward reference searching to ensure all relevant studies were included.We only included studies that were published in a peer-reviewed journal.We performed a repeat search on 1 September 2020 before submission to ensure no studies were missed.

Eligibility criteria
We included prospective and retrospective observational studies that reported the incidence of PTE in COVID-19 patients who were admitted to the ICU for treatment.We excluded individual case reports or case series on PTE in COVID-19 patients.We excluded studies that focused on reviewing all cross-sectional chest imaging, regardless of clinical indication, that had been performed for COVID-19 patients to determine the incidence of PTE in COVID-19 patients.We also excluded studies that had reported the incidence of all types of venous thromboembolism, without reporting separate incidences of pulmonary thromboembolism.Lastly, we excluded studies that were not published in peer-reviewed journals such as studies that are published in pre-print servers as they might be prone to bias.

Selection of studies and data extraction
We imported the search items into a commercially available reference manager for deduplication.Following deduplication, two authors (JN and ZL) screened the titles and abstracts for relevant studies.After screening, and obtaining the full-text manuscript of relevant studies, the same two authors reviewed them carefully for inclusion into our systematic review and meta-analysis.Disagreements that occurred during abstract and title screening, or full-text review were resolved by consensus after discussion with a third author (AC).An author (JN) extracted relevant data from the included studies, and another author (AC) veri ed the accuracy of the extracted data.Only ICU-speci c data were extracted.We extracted the following variables from the included studies: study rst author, study location, study period, study type, study population, study sample size, demographical information (age, gender, body-mass index), comorbidities (diabetes mellitus, hypertension, active malignancy, previous venous thromboembolism), laboratory parameters on admission to ICU (platelet count, D-dimer levels), venous thromboembolism prophylaxis regimes, proportion of patients on prophylactic or therapeutic anticoagulation, indication for performing PTE imaging, the incidence of PTE and follow-up period.

Study outcome
The primary outcome of this study is to estimate and report the weighted average incidence of PTE in critically ill COVID-19 patients that were admitted to the ICU.We considered a positive diagnosis of PTE only if the diagnosis was con rmed by contrast-enhanced computed tomographic imaging of the chest.The secondary outcome of this study is to assess for moderators that could potentially affect the primary outcome.

Risk of bias assessment
Two authors (JN and ZL) assessed the risk of bias of all included studies by using the ROBINS-I tool.[10] Disagreements were resolved by consensus after discussion with a third author (AC).The ROBINS-I tool was designed speci cally to assess the risk of bias in non-randomised studies in seven domains -bias due to confounding, selection bias, bias in classi cation of interventions, bias due to deviations from intended interventions, bias due to missing data, bias in measurement of outcomes, and bias in selection of reported results.Each included study would be appraised based on the ROBINS-I tool to deduce the overall risk of bias.

Data analysis
We performed statistical analysis using the meta and metafor packages with R 3.6.3(R Foundation for Statistical Computing, Vienna, Austria).A frequentist approach was utilized.Meta-analysis of proportions was performed using a random-effects model (DerSimonian and Laird) with logit transformation of observed proportions.The primary outcome was reported as proportions with their respective 95% con dence intervals (CI).We assessed statistical heterogeneity using the Cochran's Q test and I 2 statistic.In Cochran's Q test, we used a P value of less than 0.1 to represent signi cant heterogeneity of intervention effects.For the I 2 statistic, a value of more than 50% represented substantial statistical heterogeneity.We performed sensitivity analyses if appropriate.We also performed meta-regression analysis to identify possible moderators that might contribute to statistical heterogeneity.For purposes of the meta-regression, we converted median and interquartile range values to mean and standard deviation using a validated method.[11] We evaluated publication bias with a funnel plot and rank correlation test.

Study selection
A thorough and systematic search was conducted according to the pre-de ned search protocol as speci ed in the methods section of this manuscript (Fig. 1).
The search yielded a total of 2246 studies, of which 1537 studies remained after deduplication.Following title and abstract screening, we identi ed 23 studies for full-text review.After completion of full-text review, we included 14 studies into this systematic review and meta-analysis.[12][13][14][15][16][17][18][19][20][21][22][23][24][25] Risk of bias assessment Risk of bias was assessed by using the ROBINS-I tool (Table 1).[10] A single study (Fraissé et al.) was assessed to have a low risk of bias across all domains, and hence deemed to have a low overall risk of bias.[14] Nine studies were considered to have a moderate overall risk of bias, as one or more domains were deemed to be at moderate risk.[13, 16, 17, 19-22, 24, 25] Four studies were considered to have serious overall risk of bias due to the presence of missing data such as patient comorbidities and ICU characteristics.[12,15,18,23]

Prophylactic anticoagulation regime and compliance
Eleven studies reported the use of either low-molecular-weight heparin (enoxaparin, nadroparin, dalteparin or unspeci ed) or unfractionated heparin for venous thromboembolism prophylaxis in varying doses.[13,15,16,[18][19][20][21][22][23][24][25] The majority of studies had also reported information on the proportion of patients receiving therapeutic or prophylactic anticoagulation in ICU.The proportion of patients that was started on therapeutic anticoagulation in ICU varied from 0-69.2%, whilst the proportion of patients that was started on prophylactic anticoagulation varied from 30.8-100%.Overall, in ten out of the 11 studies that had al., Helms et al., Llitjos et al. and Poissy et al.), three in the Netherlands (Beun et al., Klok et al. and Middeldorp et al.), two in Italy (Lodigiani et al. and Tavazzi et al.), two in the United Kingdom (Desborough et al. and Thomas et al.), two in the United States of America (Hippensteel et al. and Maatman et al.), and one in Switzerland

Figure 1 PRISMA owchart for study selection Figure 2 Forest
Figure 1 PRISMA owchart for study selection

Table 3
[14,21]y19,21]index, DM diabetes mellitus, CKD chronic kidney disease, VTE venous thromboembolism, RRT renal replacement therapy, ECMO extracorpore membrane oxygenation, NR not reported Unless otherwise stated, all values are represented in percentages (%), mean ± standard deviation, or median (interquartile range) *Value represented as median (range) Indication for ICU admission Only four studies had reported their indication for ICU admission.[14,16,19,21]Twostudies(Fraisséetal., and Llitjos et al.) de ned their ICU admission criteria as any patient with respiratory failure.[14,19]Helmsetal. de ned their ICU admission criteria as patients who have acute respiratory distress syndrome based on the Berlin 2012 de nition, whereas the study by Maatman et al. de ned their ICU admission criteria as any patient with an oxygen saturation of 94% or less, respiratory rate of 30 breaths per minute or more, PaO 2 /FiO 2 ratio of 300 mmHg or less, or if requiring mechanical ventilation.[16,21]