COVID-19 patients with acute pulmonary embolism have a higher mortality risk: systematic review and meta-analysis based on Italian cohorts : Journal of Cardiovascular Medicine

Secondary Logo

Journal Logo

Research articles: COVID-19

COVID-19 patients with acute pulmonary embolism have a higher mortality risk: systematic review and meta-analysis based on Italian cohorts

Zuin, Marcoa,c; Rigatelli, Gianlucab; Bilato, Claudioc; Quadretti, Laurac; Roncon, Lorisb; Zuliani, Giovannia,d

Author Information
Journal of Cardiovascular Medicine: December 2022 - Volume 23 - Issue 12 - p 773-778
doi: 10.2459/JCM.0000000000001354

Abstract

Introduction

Italy was the first country in Europe to be hit hard by the coronavirus, with more than 4.7 million cases and 132 000 deaths since the beginning of the pandemic. Acute pulmonary embolism has been recognized as a frequent complication of infection,1 influencing the clinical course and outcomes of these patients.2,3 Intriguingly, a recent meta-analysis based on international investigations has reported no significant correlation between pulmonary embolism and mortality in COVID-19 patients.4 However, recent randomized controlled trials have demonstrated that thromboprophylaxis with therapeutic-dose low-molecular-weight heparin reduces the incidence of major thromboembolism and/or death in the same subjects.5,6 The aim of the present article is to perform a systematic review and meta-analysis to evaluate the mortality risk in COVID-19 Italian patients complicated by acute pulmonary embolism in the short-term period.

Materials and methods

Study design and eligibility criteria

The study was performed in accordance with the Preferred Report Items for Systematic Reviews and Meta-analyses guidelines.7 For this purpose, PubMed-MEDLINE and Scopus databases were systematically searched for articles, published in the English language and enrolling Italian cohorts of COVID-19 patients from inception through 20 October 2021, using the following Medical Subject Heading terms: ‘COVID-19’ AND ‘Pulmonary Embolism’ OR ‘Venous Thromboembolism’. Ethical approval and informed consent were not required as the study did not directly enrol human subjects.

Study selection and inclusion criteria

The selection of studies to be included in our analysis was independently conducted by two authors (M.Z. and G.Z.) in a blinded fashion. Any discrepancies in study selection were resolved by consulting a third author (L.R.). Inclusion criteria were studies enrolling subjects with a confirmed diagnosis of COVID-19; based on Italian cohorts; stratifying the population as patients with and without COVID-19 infection; providing data on the short-term mortality (in hospital or 30-day mortality). Conversely, randomized controlled trials, case reports, review articles, editorials/letters, case series with fewer than 10 participants, international multicentric studies including as a part of the entire sample also Italian patients and studies including duplicate populations, if any, were excluded. Moreover, references from the included studies were screened to potentially identify other investigations meeting the inclusion criteria.

Data extraction and quality assessment

Data were independently extracted by two authors (G.R. and L.Q.) in a blinded fashion. Also in this case, any discrepancies were resolved by consulting a third author (L.R.). For all investigations included in the study we extracted the type of investigation, sample size, number of acute pulmonary embolism events, mortality rate, males percentage, mean age, presence of pulmonary embolism risk factors (such as cancer, obesity and previous venous thromboembolic events), concomitant comorbidities already associated with a poor outcome in COVID-19 patients including arterial hypertension8 and diabetes mellites9 and administration of prophylactic or therapeutic anticoagulation treatments. The quality of the included studies was graded using the Newcastle–Ottawa quality assessment scale.10

Data synthesis and analysis

Continues variables were expressed as mean ± SD or as a mean with relative interquartile range while categorical variables were presented as numbers and relative percentages. The cumulative incidence of acute pulmonary embolism was defined and calculated as the ratio between COVID-19 patients experiencing pulmonary embolism (n) and the number of patients enrolled in each study (N). Mortality risk data were pooled using the Mantel–Haenszel random effects models with odds ratio (OR) as the effect measure with 95% confidence interval (CI). Heterogeneity among studies was assessed using the Higgins and Thomson I2 statistic where I2 values correspond to the following levels of heterogeneity: low (<25%), moderate (25%–75%) and high (>75%). The presence of potential publication bias was verified by visual inspection of the funnel plot. Due to the low number of the included studies (<10), small-study bias was not examined as our analysis was underpowered to detect such bias. However, a predefined sensitivity analysis (leave-one-out analysis) was performed by removing one study at a time, to evaluate the stability of our results regarding the mortality risk. All meta-analyses were conducted using Comprehensive Meta-Analysis software, version 3 (Biostat, Tampa, Florida, USA).

Results

Search results study characteristics

Initial search resulted in 4951 articles. A total of 3623 articles were retrieved after excluding duplicates. The initial screening excluded 2248 articles because they did not meet inclusion criteria, leaving 1375 articles to assess for eligibility. Subsequently, after evaluation of the full-text articles, 1367 were excluded and 8 investigations met the inclusion criteria (Fig. 1).11–18

F1
Fig. 1:
Preferred Report Items for Systematic Reviews and Meta-analyses flowchart. Articles excluded because not provided mortality outcomes; ∗∗Articles excluded because not based on Italian cohorts.

Study characteristics

Overall, 1681 Italian patients with a confirmed diagnosis of COVID-19 infection (mean age 64.9 years old, 1125 males) were included in the analysis. The general characteristics of patients enrolled are shown in Table 1. In all patients, the diagnosis of acute pulmonary embolism was performed by using computed tomography angiography. The mortality rate and incidence of acute pulmonary embolism were 19.8% (n = 334) and 19.0% (n = 320), respectively.11–18 Despite concomitant comorbidities not being systematically evaluated by all the investigations, arterial hypertension and diabetes mellitus were the most common. Data regarding the administration of prophylactic anticoagulation, provided by four studies (n = 1221),12,14,17,18 showed that this anticoagulant regimen was used in 46.0% of cases (n = 562). Conversely, only two investigations (n = 308) provided data regarding the use of therapeutical anticoagulant treatment which was administered in 15.2% of patients (n = 47).12,14

Table 1 - General characteristics of the population enrolled
Author Type Number of pts, N PE, n Mortality, N (%) Males N (%) Mean age, years (IQR) Cancer, N, (%) Obesity, n (%) HT, N (%) DM, N (%) Previous VTE, N (%) Anticoagulation, N (%) NOS
Cau et al. 11 Retro S 84 26 3 (3.5) 57 (68.0) 60.4 (16.0) 8 (9.0) NR 45 (53.0) 25 (30.0) NR NR 7
Filippi et al. 12 Retro S 267 50 47 (17.6) 172 (64.4) 69 17 (6.3) 48 (17.9) NR NR 8 (2.9) P: 192 (71.9)T: 18 (6.7) 8
Ippolito et al. 13 Retro S 170 76 22 (12.9) 116 (68.2) 63 (12.0) NR NR NR NR NR NR 6
Polo Friz et al. 14 Retro S 41 8 2 (4.8) 11 (26.8) 71.7 (63–76.2) 3 (7.2) NR 29 (70.7) 11 (26.8) NR P: 4 (9.7)T:29 (70.7) 7
Scarduelli et al. 15 Retro S 92 11 11 (11.9) 71 (77.1) 58 (11) NR 42 (45.0) 43 (46.0) 18 (19.0) NR NR 7
Ameri et al. 16 Retro Multi 689 52 164 (23.8) 487 (69.4) 67.3 (13.2) NR NR 398 (56.9) 157 (23.0) NR P: 185 (26.8) 7
Scudiero et al. 17 Retro Multi 224 32 68 (30.3) 127 (62.0) 69 (14.0) 27 (12.0) NR 137 (61.0) 63 (28.0) NR P: 181 (81.0) 7
Valle et al. 18 Retro S 114 65 17 (14.9) 84 (73.7) 61 (51.2–66) 42 (36.8) 13 (11.4) 41 (35.9) 17 (14.9) NR NR 6
DM, diabetes mellitus; HT, arterial hypertension; IQR, interquartile range; NOS, Newcastle–Ottawa quality assessment scale; NR, not reported; P, prophylactic anticoagulation; PE, pulmonary embolism; pts, patients; T, therapeutic anticoagulation; VTE, venous thromboembolism.

Mortality risk in COVID-19 patients with acute pulmonary embolism

On pooled analysis, patients with acute pulmonary embolism showed a significantly higher mortality risk in the short-term period (OR: 1.76, 95% CI: 1.26–2.47, P = 0.001, I2 = 0%) (Fig. 1, panel a).11–18 The visual inspection of the relative funnel plot did not reveal significant evidence of publication bias (Fig. 2, panel b). To evaluate the robustness of the association results, we performed a leave-one-out sensitivity analysis by iteratively removing one study at a time and recalculating the summary OR. The summary ORs remained stable (ranging between OR: 1.60, 95% CI: 1.10–2.32, P = 0.001 and OR: 1.85, 95% CI: 1.32–2.60, P < 0.001), indicating that our results were not driven by any single study.

F2
Fig. 2:
(a) Forest plot evaluating the mortality risk in COVID-19 patients with acute pulmonary embolism using a random-effect model. (b) Funnel plot for the mortality risk in COVID-19 patients with acute pulmonary embolism using a random-effect model.

Discussion

The results of present analysis demonstrated that Italian subjects with COVID-19 infection and concomitant acute pulmonary embolism have a higher mortality risk in the short-term period. Specifically, an additional 76% risk of death was observed in COVID-19 pulmonary embolism patients compared with those without.11–18 Our findings contradict those presented by Gomez et al.,4 who evidenced a comparable risk of mortality between pulmonary embolism and nonpulmonary embolism patients. More precisely, the authors presented their results into a meta-analysis based on international studies; however, they did not perform any subanalysis for different countries. As known, Italy was the first country outside China to experience the impact of the COVID-19 pandemic. Therefore, we decided to investigate the impact of acute pulmonary embolism on Italian COVID-19 patients since our country has been hit hard by the pandemic, especially during the first phase. Moreover, considering that pulmonary embolism, and more in general COVID-19 complications, largely depend on the presence of comorbidities as well as the age of patients, it would be of interest to investigate the prognostic role of thromboembolic events in such a scenario being that Italy is one of the oldest European countries with patients having a high prevalence of comorbidities.

The scant knowledge of underlying pathophysiological mechanisms and potential supportive treatment able to reduce the onset of complications and mortality risk in COVID-19 patients were largely unknown, especially during the first pandemic wave. These aspects may have led to higher complication rates as well as associated mortality events. However, also the demographical features of the population and the prevalence of concomitant comorbidities may have influenced the onset of thromboembolic complications and relative outcomes, especially in patients with previous cardiovascular disease.19–24 Indeed, Italian mortality data demonstrated that there was a strong geographical pattern, mainly involving the Italian northern regions (Lombardy, Veneto and Emilia-Romagna) as well as age and sex distribution, being that older males were more frequently infected and died.25,26 Intriguingly, these issues have been also associated, per se, with a higher mortality risk in COVID-19 patients with acute pulmonary embolism and reflect the main characteristic of the population analysed. In fact, older COVID-19 males are at higher risk of acute pulmonary embolism and mortality due to the underling infection.4,27,28 On the contrary, the revised investigations were conducted only during the first phase of the pandemic, in which the scant use of adequate anticoagulant treatments may have also contributed to the higher mortality risk in Italian COVID-19 patients with concomitant pulmonary embolism, as demonstrated by our results. Our findings confirm the results of several recent investigations which demonstrated that the clinical outcomes in patients with SARS-CoV-2 infection are closely related to the burden of associated cardiovascular comorbidities and complications during the infection.29–32 Understanding the risk factors associated with a poor outcome in these patients remains critical to promptly identify vulnerable populations who would require prioritization in treatment and prevention and close monitoring if infected.

Limitations

Our study has several limitations related to the design of the studies reviewed with all inherited biases and the numbers of investigations on the issue. In fact, a limited number of Italian studies have analysed the relationship between acute pulmonary embolism and mortality risk in COVID-19 patients, partially limiting our results and conclusions. However, the absence of heterogeneity confirmed the robustness of our findings. Moreover, we cannot assess the timing of acute pulmonary embolism onset, diagnosis and anticoagulant regimen used; these issues may have significantly influenced the incidence of acute pulmonary embolism and therefore the related mortality.

Conclusion

In Italian COVID-19 patients, acute pulmonary embolism was present in one patient out of four and significantly associated with a higher mortality risk in the short-term period. The prompt identification of acute pulmonary embolism in these patients remains critical to promptly identify vulnerable populations who would require prioritization in treatment and prevention and close monitoring.

Supplementary File 1. PRISMA checklist, https://links.lww.com/JCM/A479.

Conflicts of interest

There are no conflicts of interest.

References

1. Roncon L, Zuin M, Barco S, et al. Incidence of acute pulmonary embolism in COVID-19 patients: systematic review and meta-analysis. Eur J Intern Med 2020; 82:29–37.
2. Zhang C, Shen L, Le KJ, et al. Incidence of venous thromboembolism in hospitalized coronavirus disease 2019 patients: a systematic review and meta-analysis. Front Cardiovasc Med 2020; 7:151.
3. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020; 18:1094–1099.
4. Gómez CA, Sun CK, Tsai IT, et al. Mortality and risk factors associated with pulmonary embolism in coronavirus disease 2019 patients: a systematic review and meta-analysis. Sci Rep 2021; 11:16025.
5. Spyropoulos AC, Goldin M, Giannis D, et al. HEP-COVID Investigators. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern Med 2021; 181:1612–1620. [Epub ahead of print].
6. Sholzberg M, Tang GH, Rahhal H, et al. RAPID Trial Investigators. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ 2021; 375:n2400.
7. Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6:e1000097.
8. Zuin M, Rigatelli G, Zuliani G, Rigatelli A, Mazza A, Roncon L. Arterial hypertension and risk of death in patients with COVID-19 infection: systematic review and meta-analysis. J Infect 2020; 81:e84–e86.
9. Roncon L, Zuin M, Rigatelli G, Zuliani G. Diabetic patients with COVID-19 infection are at higher risk of ICU admission and poor short-term outcome. J Clin Virol 2020; 127:104354.
10. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses, 2012. http://wwwohrica/programs/clinical_epidemiology/oxfordasp. [Accessed 24 October 2021]
11. Cau R, Pacielli A, Fatemeh H, et al. Complications in COVID-19 patients: characteristics of pulmonary embolism. Clin Imaging 2021; 77:244–249.
12. Filippi L, Sartori M, Facci M, et al. Pulmonary embolism in patients with COVID-19 pneumonia: when we have to search for it? Thromb Res 2021; 206:29–32.
13. Ippolito D, Giandola T, Maino C, et al. Acute pulmonary embolism in hospitalized patients with SARS-CoV-2-related pneumonia: multicentric experience from Italian endemic area. Radiol Med 2021; 126:669–678.
14. Polo Friz H, Gelfi E, Orenti A, et al. Acute pulmonary embolism in patients presenting pulmonary deterioration after hospitalisation for noncritical COVID-19. Intern Med J 2021; 51:1236–1242.
15. Scarduelli C, Inglese F, Beccaria M, et al. Pulmonary embolism in patients with severe COVID-19 treated with intermediate- to full-dose enoxaparin: a retrospective study. Monaldi Arch Chest Dis 2021; 91: [Epub ahead of print].
16. Ameri P, Inciardi RM, Di Pasquale M, et al. Pulmonary embolism in patients with COVID-19: characteristics and outcomes in the Cardio-COVID Italy multicenter study. Clin Res Cardiol 2021; 110:1020–1028.
17. Scudiero F, Silverio A, Di Maio M, et al. Cov-IT Network. Pulmonary embolism in COVID-19 patients: prevalence, predictors and clinical outcome. Thromb Res 2021; 198:34–39.
18. Valle C, Bonaffini PA, Dal Corso M, et al. Association between pulmonary embolism and COVID-19 severe pneumonia: experience from two centers in the core of the infection Italian peak. Eur J Radiol 2021; 137:109613.
19. Ghio S, Montalto C, Pagnesi M, et al. High troponin levels in patients hospitalized for coronavirus disease 2019: a maker or a marker of prognosis? J Cardiovasc Med (Hagerstown) 2021; 22:828–831.
20. Arcari L, Luciani M, Cacciotti L, et al. Coronavirus disease 2019 in patients with cardiovascular disease: clinical features and implications on cardiac biomarkers assessment. J Cardiovasc Med (Hagerstown) 2021; 22:832–839.
21. Calcaterra G, Bassareo PP, Barilla’ F, Romeo F, Mehta JL. Concerning the unexpected prothrombotic state following some coronavirus disease 2019 vaccines. J Cardiovasc Med (Hagerstown) 2022; 23:71–74.
22. Zorzi A, Vio R, Rivezzi F, et al. Characteristics and hospital course of patients admitted for acute cardiovascular diseases during the coronavirus disease-19 outbreak. J Cardiovasc Med (Hagerstown) 2021; 22:29–35.
23. Frattini S, Maccagni G, Italia L, Metra M, Danzi GB. Coronavirus disease 2019 and cardiovascular implications. J Cardiovasc Med (Hagerstown) 2020; 21:725–732.
24. Inama G, Dodi C, Provini M, et al. Coronavirus disease 2019 infection in patients with recent cardiac surgery: does chronic anticoagulant therapy have a protective effect? J Cardiovasc Med (Hagerstown) 2020; 21:765–771.
25. Scortichini M, Schneider Dos Santos R, De’ Donato F, et al. Excess mortality during the COVID-19 outbreak in Italy: a two-stage interrupted time-series analysis. Int J Epidemiol 2021; 49:1909–1917.
26. Caselli G, Egidi V. Gender differences in COVID-19 cases and death rates in Italy. Ital J Gender Specific Med 2020; 6:96–99.
27. Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA 2020; 323:1775–1776.
28. Henrina J, Santosa Putra IC, Cahyadi I, et al. Clinical characteristics and outcomes of venous thromboembolism in patients hospitalized for COVID-19: systematic review and meta-analysis. Thrombosis Update 2021; 2:100037.
29. Zuin M, Rigatelli G, Bilato C, Cervellati C, Zuliani G, Roncon L. Dyslipidaemia and mortality in COVID-19 patients: a meta-analysis. QJM 2021; 114:390–397.
30. Zuin M, Rigatelli G, Bilato C, Zuliani G, Roncon L. Heart failure as a complication of COVID-19 infection: systematic review and meta-analysis. Acta Cardiol 2021; 77:107–113.
31. Zuin M, Rigatelli G, Bilato C, Zanon F, Zuliani G, Roncon L. Preexisting atrial fibrillation is associated with increased mortality in COVID-19 patients. J Interv Card Electrophysiol 2021; 62:231–238.
32. Zuin M, Rigatelli G, Zuliani G, Bilato C, Zonzin P, Roncon L. Incidence and mortality risk in coronavirus disease 2019 patients complicated by acute cardiac injury: systematic review and meta-analysis. J Cardiovasc Med (Hagerstown) 2020; 21:759–764.
Keywords:

COVID-19; mortality; pulmonary embolism

Supplemental Digital Content

© 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.