Mortality related to pulmonary embolism in the United States before and during the COVID-19 pandemic: An analysis of the CDC Multiple Cause of Death database

Background: The COVID-19 pandemic caused a large number of excess deaths. COVID-19 emerged as a prothrombotic disease often complicated by pulmonary embolism (PE). In light of this, we hypothesized that PErelated mortality rates (stable before the pandemic) would be characterized by an increasing trend following the COVID-19 outbreak. Purpose(s): To investigate the mortality rates associated with PE among deaths with or without COVID-19 during the 2020 pandemic in the United States (US). Method(s): For this retrospective epidemiological study, we analyzed public medically certified vital registration data (death certificates encompassing underlying and multiple causes of death) from the Mortality Multiple Cause-of-Death database provided by the Division of Vital Statistics of the US Centers for Disease Control and Prevention (CDC;US, 2018-20). We investigated the time trends in monthly PE-related crude mortality rates for 2018-2019 and for 2020 (the latter associated vs. not associated with COVID-19), utilizing annual national population totals from the US Census Bureau. Second, we calculated the PE-related proportionate mortality among COVID-19 deaths (overall and limited to autopsy-based diagnosis). We performed subgroup analyses based on age groups, sex and race. Result(s): During 2020, 49,423 deaths in association with PE were reported, vs. 39,450 in 2019 and 38,215 in 2018. The crude PE-related mortality rate without COVID-19 was 13.3 per 100,000 population in 2020 compared to 11.7 in 2018 and 12.0 in 2019 (Figure 1A). The PE-related mortality rate with COVID-19 was 1.6 per 100,000 population in 2020. Among non- COVID-19-related deaths, the crude PE-related mortality rate was higher in women;among COVID-19-related deaths, it was higher in men. PE-related mortality rates were approximately two-fold higher among black (vs. white) general population irrespective of COVID-19 status (Figures 1B and 1C). Among COVID-19 deaths, PE-related deaths corresponded to 1.4% of total;the value rose to 6.0% when an autopsy was performed. This figure was higher in men and its time evolution is depicted in Figure 2A. The proportionate mortality of PE in COVID-19 deaths was higher for younger age groups (15-44 years) compared to non-COVID-19-related deaths (Figure 2B). Conclusion(s): In 2020, an overall 20%-increase in PE-related mortality was reported, not being limited to patients with COVID-19. Our findings could be interpreted in the context of undiagnosed COVID-19 cases, uncounted late sequelae, and possibly sedentary lifestyle and avoidance of healthcare facilities during the pandemic that may have prevented timely diagnosis and treatment of other diseases. Whether vaccination programs had an impact on PE-associated mortality in the year 2021, remains to be determined.

Incidence and impact of anticoagulation-associated abnormal menstrual bleeding in women after venous thromboembolism.

Preliminary data and clinical experience have suggested an increased risk of abnormal uterine bleeding (AUB) in women of reproductive age treated with anticoagulants, but solid data are lacking. The TEAM-VTE study was an international multicenter prospective cohort study in women aged 18 to 50 years diagnosed with acute venous thromboembolism (VTE). Menstrual blood loss was measured by pictorial blood loss assessment charts at baseline for the last menstrual cycle before VTE diagnosis and prospectively for each cycle during 3 to 6 months of follow-up. AUB was defined as an increased score on the pictorial blood loss assessment chart (>100 or >150) or self-reported AUB. AUB-related quality of life (QoL) was assessed at baseline and the end of follow-up using the Menstrual Bleeding Questionnaire. The study was terminated early because of slow recruitment attributable to the COVID-19 pandemic. Of the 98 women, 65 (66%) met at least one of the 3 definitions of AUB during follow-up (95% confidence interval [CI], 57%-75%). AUB occurred in 60% of women (36 of 60) without AUB before VTE diagnosis (new-onset AUB; 95% CI, 47%-71%). Overall, QoL decreased over time, with a mean Menstrual Bleeding Questionnaire score increase of 5.1 points (95% CI, 2.2-7.9), but this decrease in QoL was observed only among women with new-onset AUB. To conclude, 2 of every 3 women who start anticoagulation for acute VTE experience AUB, with a considerable negative impact on QoL. These findings should be a call to action to increase awareness and provide evidence-based strategies to prevent and treat AUB in this setting. This was an academic study registered at www.clinicaltrials.gov as #NCT04748393; no funding was received.

PREVALENCE OF CEREBROVASCULAR MRI MARKERS IN HOSPITALIZED PATIENTS WITH COVID-19

Background and aims: COVID-19 is complicated by symptomatic ischemic stroke in 1% to 3% in small selected studies of hospitalized patients. We aimed to assess the prevalence of cerebrovascular MRI markers and its causes in large samples of unselected patients with COVID-19, compared to healthy controls, which is unknown. Methods: CORONIS is an ongoing observational cohort study in adult hospitalized patients with COVID-19. Patients without clinically overt stroke undergo standardized questionnaires, cognitive assessment, blood sampling, cardiac echo, telemetry and brain MRI within 90 days after COVID-19 infection. Controls undergo standardized questionnaires and brain MRI. MRI markers include (acute) ischemic lesions, microbleeds, white matter hyperintensities, and intracranial vessel wall abnormalities and contrast enhancement. Brain MRI will be repeated after 3 months in a subset of patients. Cognitive function and functional outcome are assessed after 3 and 12 months after baseline measurements. Results: This is an ongoing study with preliminary results. Between April and December 2021, we recruited 88 patients with a median age of 59 years (IQR 49.3-67.8), of whom 59 (67%) are men and 25 (28%) had been admitted to the ICU. DWI lesions were found in 1 patient (1%), microbleeds in 22 patients (23%) and white matter hyperintensities in 66 (75%). Intracranial vessel wall enhancement was seen in 16%. Control results will follow. Conclusions: The CORONIS study will provide insight into the frequency and risk factors of MRI markers of cerebrovascular lesions and its relation with long-term functional outcome in hospitalized adult patients with COVID-19.

Dealing with COVID-19-associated coagulopathy

COVID-19 is associated with a high prevalence of activation of the coagulation cascade. It has been suggested that this so-called COVID-19-associated coagulopathy is predictive of a poor outcome and of mortality. Consensus documents on how to manage patients with COVID-19-associated coagulopathy are based on the limited number of mainly retrospective studies that is currently available, and for this reason the recommendations are not always consistent with one another. In this article, we review the first studies into COVID-19-associated coagulopathy and give the most important do's and don'ts for diagnostics and the daily management of coagulopathy and the prevention of complications in patients with, or with strongly-suspected, COVID-19 in Dutch clinical practice.

Diagnostic management of suspected pulmonary embolism in patients with COVID-19: A prospective cohort study

Background : Diagnostic strategies for suspected pulmonary embolism (PE) have not been prospectively evaluated in COVID-19 patients. Aims : Evaluate diagnostic strategies for suspected PE in patients with COVID-19. Methods : Prospective, multicenter, cohort study in 708 patients with suspected PE and (suspected) COVID-19, without anticoagulant therapy, from 14 hospitals (March 1 -October 29, 2020). The study was approved by Institutional Review Boards of these hospitals and informed consent was obtained by opt-out approach. Different management protocols for suspected PE were used in the participating hospitals: YEARS algorithm, computed tomography pulmonary angiography (CTPA) only, or Wells rule with variable D-dimer threshold. We evaluated the safety (3-month failure rate) and efficiency (number of CTPAs avoided) of the three strategies. Results : Baseline characteristics are presented in Table 1;PE prevalence was 28%. YEARS was applied in 36%, Wells rule in 4.2% and CTPA only in 52%;7.3% was not tested because of hemodynamic instability. Within YEARS, PE was considered excluded without CTPA in 29%, of which one patient developed non-fatal PE during followup (failure rate 1.4%;95%CI 0.03-7.4;Table 2). 117 patients had a negative CTPA within YEARS (46%), of whom 10 were diagnosed with non-fatal venous thromboembolism (VTE) during follow-up (failure rate 8.5%;95%CI 4.2-15;Table 2). In patients imaged with CTPA only, 65% had an initial negative CTPA, of whom 10 patients were diagnosed with non-fatal VTE during follow-up (failure rate 4.1%;95%CI 2.0-7.5). CTPA was avoided in 2 patients (6.7%) managed with Wells rule. Conclusions : CTPA could be avoided in 29% of patients managed by YEARS, with a low failure rate (1.4%). The failure rate of a negative CTPA, used as a sole test or within YEARS, was higher than in a non-COVID-19 population and warrants ongoing suspicion in these patients. Our results underline the applicability of the YEARS algorithm in COVID-19 patients with suspected PE.

Challenges in the diagnostic approach of suspected pulmonary embolism in COVID-19 patients.

Accumulating studies on COVID-19 patients report high incidences of thrombotic complications, but guidance on the best diagnostic approach for suspected pulmonary embolism (PE) in COVID-19 patients is lacking. Diagnosing PE in these patients is challenging as signs and symptoms of PE and COVID-19 show wide overlap, D-dimer levels are often elevated in the absence of thrombosis and computed tomography pulmonary angiography (CTPA) may be unfeasible in the case of severe renal impairment and/or hemodynamic instability.This narrative review discusses available literature and guidelines on current diagnostic algorithms for suspected PE in special patient populations, in particular COVID-19. A special focus is on reviewing the literature aimed at identifying symptoms with a high suspicion for PE and on the diagnostic performance of diagnostic algorithms for suspected PE in the setting of COVID-19.Based on available literature, the index of suspicion for PE should be high in the case of unexplained abrupt worsening of respiratory status, typical symptoms of deep-vein thrombosis and/or acute unexplained right ventricular dysfunction. Despite the lack of prospective diagnostic management studies, we propose to adhere to current diagnostic algorithms applying assessment of pretest probability and D-dimer testing as available evidence suggests that these might be considered safe. Preferably, algorithms using adjusted D-dimer thresholds are recommended as it likely improves the yield of the clinical decision rule/D-dimer combination.

Effect of anticoagulant therapy in COVID-19 patients.

BACKGROUND: In patients hospitalised with COVID-19, an increased incidence of thromboembolic events, such as pulmonary embolism, deep vein thrombosis and stroke, has been reported. It is unknown whether anticoagulation can prevent these complications and improve outcome. METHODS: A systematic literature search was performed to answer the question: What is the effect of (prophylactic and therapeutic dose) anticoagulation therapy in COVID-19 patients on cardiovascular and thromboembolic complications and clinical outcome? Relevant outcome measures were mortality (crucial), hospital admission, length of stay, thromboembolic complications (pulmonary embolism, stroke, transient ischaemic attack), need for mechanical ventilation, acute kidney injury and use of renal replacement therapy. Medline and Embase databases were searched with relevant search terms until 17 July 2020. After systematic analysis, eight studies were included. Analysis was stratified for the start of anticoagulation before or during hospital admission. RESULTS: There was insufficient evidence that therapeutic anticoagulation could improve the outcome in patients hospitalised with COVID-19. None of the studies demonstrated improved mortality, except for one very small Italian study. Furthermore, none of the studies showed a positive effect of anticoagulation on other outcome measures in COVID-19, such as ICU admission, length of hospital stay, thromboembolic complications, need for mechanical ventilation, acute kidney failure or need for renal replacement therapy, except for two studies demonstrating an association between anticoagulation and a lower incidence of pulmonary embolism. However, the level of evidence of all studies varied from 'low' to 'very low', according to the GRADE methodology. CONCLUSION: Analysis of the literature showed that there was insufficient evidence to answer our objective on the effect of anticoagulation on outcome in COVID-19 patients, especially due to the low scientific quality of the described studies. Randomised controlled studies are needed to answer this question.

Prophylaxis and treatment of COVID-19 related venous thromboembolism.

COVID-19 pneumonia has been associated with high rates of thrombo-embolic complications, mostly venous thromboembolism (VTE), which is thought to be a combination of conventional VTE and in situ immunothrombosis in the pulmonary vascular tree. The incidence of thrombotic complications is dependent on setting (intensive care unit (ICU) versus general ward) and the threshold for performing diagnostic tests (screening versus diagnostic algorithms triggered by symptoms). Since these thrombotic complications are associated with in-hospital mortality, all current guidelines and consensus papers propose pharmacological thromboprophylaxis in all hospitalized patients with COVID-19. Several trials are ongoing to study the optimal intensity of anticoagulation for this purpose. As for the management of thrombotic complications, treatment regimens from non-COVID-19 guidelines can be adapted, with choice of anticoagulant drug class dependent on the situation. Parenteral anticoagulation is preferred for patients on ICUs or with impending clinical deterioration, while oral treatment can be started in stable patients. This review describes current knowledge on incidence and pathophysiology of COVID-19 associated VTE and provides an overview of guideline recommendations on thromboprophylaxis and treatment of established VTE in COVID-19 patients.

Incidence of thrombotic complications and overall survival in hospitalized patients with COVID-19 in the second and first wave.

INTRODUCTION: In the first wave, thrombotic complications were common in COVID-19 patients. It is unknown whether state-of-the-art treatment has resulted in less thrombotic complications in the second wave. METHODS: We assessed the incidence of thrombotic complications and overall mortality in COVID-19 patients admitted to eight Dutch hospitals between September 1st and November 30th 2020. Follow-up ended at discharge, transfer to another hospital, when they died, or on November 30th 2020, whichever came first. Cumulative incidences were estimated, adjusted for competing risk of death. These were compared to those observed in 579 patients admitted in the first wave, between February 24th and April 26th 2020, by means of Cox regression techniques adjusted for age, sex and weight. RESULTS: In total 947 patients with COVID-19 were included in this analysis, of whom 358 patients were admitted to the ICU; 144 patients died (15%). The adjusted cumulative incidence of all thrombotic complications after 10, 20 and 30 days was 12% (95% confidence interval (CI) 9.8-15%), 16% (13-19%) and 21% (17-25%), respectively. Patient characteristics between the first and second wave were comparable. The adjusted hazard ratio (HR) for overall mortality in the second wave versus the first wave was 0.53 (95%CI 0.41-0.70). The adjusted HR for any thrombotic complication in the second versus the first wave was 0.89 (95%CI 0.65-1.2). CONCLUSIONS: Mortality was reduced by 47% in the second wave, but the thrombotic complication rate remained high, and comparable to the first wave. Careful attention to provision of adequate thromboprophylaxis is invariably warranted.

Clinical and computed tomography characteristics of COVID-19 associated acute pulmonary embolism: A different phenotype of thrombotic disease?

INTRODUCTION: COVID-19 infections are associated with a high prevalence of venous thromboembolism, particularly pulmonary embolism (PE). It is suggested that COVID-19 associated PE represents in situ immunothrombosis rather than venous thromboembolism, although the origin of thrombotic lesions in COVID-19 patients remains largely unknown. METHODS: In this study, we assessed the clinical and computed tomography (CT) characteristics of PE in 23 consecutive patients with COVID-19 pneumonia and compared these to those of 100 consecutive control patients diagnosed with acute PE before the COVID-19 outbreak. Specifically, RV/LV diameter ratio, pulmonary artery trunk diameter and total thrombus load (according to Qanadli score) were measured and compared. RESULTS: We observed that all thrombotic lesions in COVID-19 patients were found to be in lung parenchyma affected by COVID-19. Also, the thrombus load was lower in COVID-19 patients (Qanadli score -8%, 95% confidence interval [95%CI] -16 to -0.36%) as was the prevalence of the most proximal PE in the main/lobar pulmonary artery (17% versus 47%; -30%, 95%CI -44% to -8.2). Moreover, the mean RV/LV ratio (mean difference -0.23, 95%CI -0.39 to -0.07) and the prevalence of RV/LV ratio >1.0 (prevalence difference -23%, 95%CI -41 to -0.86%) were lower in the COVID-19 patients. CONCLUSION: Our findings therefore suggest that the phenotype of COVID-19 associated PE indeed differs from PE in patients without COVID-19, fuelling the discussion on its pathophysiology.

Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis.

INTRODUCTION: We recently reported a high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 admitted to the intensive care units (ICUs) of three Dutch hospitals. In answering questions raised regarding our study, we updated our database and repeated all analyses. METHODS: We re-evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction and/or systemic arterial embolism in all COVID-19 patients admitted to the ICUs of 2 Dutch university hospitals and 1 Dutch teaching hospital from ICU admission to death, ICU discharge or April 22nd 2020, whichever came first. RESULTS: We studied the same 184 ICU patients as reported on previously, of whom a total of 41 died (22%) and 78 were discharged alive (43%). The median follow-up duration increased from 7 to 14 days. All patients received pharmacological thromboprophylaxis. The cumulative incidence of the composite outcome, adjusted for competing risk of death, was 49% (95% confidence interval [CI] 41-57%). The majority of thrombotic events were PE (65/75; 87%). In the competing risk model, chronic anticoagulation therapy at admission was associated with a lower risk of the composite outcome (Hazard Ratio [HR] 0.29, 95%CI 0.091-0.92). Patients diagnosed with thrombotic complications were at higher risk of all-cause death (HR 5.4; 95%CI 2.4-12). Use of therapeutic anticoagulation was not associated with all-cause death (HR 0.79, 95%CI 0.35-1.8). CONCLUSION: In this updated analysis, we confirm the very high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 pneumonia.

Incidence of thrombotic complications in critically ill ICU patients with COVID-19.

INTRODUCTION: COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. Reports on the incidence of thrombotic complications are however not available. METHODS: We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital. RESULTS: We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020. All patients received at least standard doses thromboprophylaxis. The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%). PE was the most frequent thrombotic complication (n = 25, 81%). Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic complications. CONCLUSION: The 31% incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high. Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence.