key: cord-0757991-7oiihj71
authors: Faries, Christopher M.; Rao, Ajit; Ilonzo, Nicole; Hwong, Songhon; Krishnan, Prakash; Farhan, Serdar; Ting, Windsor; Vouyouka, Ageliki G.; Tadros, Rami O.; Marin, Michael L.; Faries, Peter L.
title: Follow-up after acute thrombotic events following COVID-19 infection
date: 2021-09-28
journal: J Vasc Surg
DOI: 10.1016/j.jvs.2021.08.092
sha: aa15086585fe07216a4266d1dd6879fdf50b4f4d
doc_id: 757991
cord_uid: 7oiihj71

OBJECTIVE: COVID-19 infection results in a hypercoagulable state predisposing patients to thrombotic events. We report the 3- and 6- month follow-up of 27 patients who experienced acute arterial thrombotic events in the setting of COVID-19 infection. METHODS: Data was prospectively collected and maintained for all vascular surgery consultations in the Mount Sinai Health System from patients who presented between March 16th and May 5th, 2020. RESULTS: 27 patients experienced arterial thrombotic events. Average length of stay was 13.3 ± 15.4 days. 14 patients were treated with open surgical intervention, 6 were treated with endovascular intervention, and 7 were treated with anticoagulation only. At 3-month follow-up, 11 patients (40.7%) were deceased. 9 patients who expired did so during the initial hospital stay. The 3-month cumulative primary patency rate for all interventions was 72.2%, and the 3-month primary patency rates for open surgical and endovascular interventions were 66.7 and 83.3 respectively. There were 9 (33.3%) readmissions within 3 months. 6-month follow-up was available in 25 (92.6%) patients. At 6-month follow-up, 12 (48.0%) patients were deceased, and the cumulative primary patency rate was 61.9%. The 6-month primary patency rates of open surgical and endovascular interventions were 66.7% and 55.6% respectively. The limb-salvage rate at both 3- and 6-months was 89.2%. CONCLUSION: Patients with COVID-19 infections who experienced thrombotic events saw high complication and mortality rates with relatively low patency rates.

There was a 72.2% primary patency rate, 40.7% mortality rate, 89.2% limb-salvage rate at 3-12 months, and a 61.9% patency rate, 48.0% mortality rate, 89.2% limb-salvage rate at 6-months in 13 27 patients with acute thrombotic events associated with COVID-19. These patients saw high 14 complication and mortality rates with relatively low patency. 15

Introduction 1 COVID-19 has a wide range of recognized presentations from asymptomatic carriers to 2 upper respiratory symptoms, and in severe cases Acute Respiratory Distress Syndrome (ARDS), 3 multi-organ failure, and death. However, there is increasing evidence documenting the COVID-4 19 associated thrombotic complications in the central, cerebral, and peripheral circulation. 1 5

These events are frequently seen in patients without conventional cardiovascular risk factors. 6

Immediate outcomes following COVID-19 associated acute thrombotic events appear to 7 be poor, with reported in-hospital mortality rates ranging from 33% to 46% and early rates of 8 limb loss ranging from 6.7% to 25%. [2] [3] [4] [5] . However, there is very limited data regarding follow-up 9 of patients after medical treatment or surgical or endovascular intervention. In this study, we 10 report 3-month and 6-month follow-up of patients who were treated for acute thrombotic arterial 11 events in the setting of COVID-19 infection. The primary outcome was primary patency of the vascular intervention. Secondary 22 outcomes included mortality, hospital length of stay, and limb salvage. General anesthesia was 23

used predominantly for open surgical intervention and local or regional anesthesia was used 1 predominantly for endovascular intervention. Patency was assessed using duplex ultrasound, 2 computed tomography, angiogram, doppler ultrasound, and pulse examination. Clinical 3 indicators of patency including freedom from tissue loss or recurrent rest pain were also 4 documented. Mild COVID-19 infection was defined as a hospitalized patient with SpO2 greater 5 than 94% on room air and no radiographic evidence of pneumonia. Moderate COVID-19 6 infection was defined as hospitalized patients with hypoxia (SpO2 less than or equal to 94% 7 requiring supplemental oxygen) or radiographic evidence of pneumonia. Severe COVID-19 8 infection was defined as patient requiring more than nasal cannula to maintain oxygen saturation. 9

These definitions are adopted from established classifications. 7,8 10

To assess for significance in patient outcomes, univariate analysis was performed using 13

Pearson χ2 and Fisher exact tests for categorical variables and Student t-test for continuous 14 variables. Kaplan-Meier life tables were used to assess primary patency rates and limb-salvage 15 rates. Patients whose initial intervention was primary amputation without attempted prior 16 revascularization were not included in limb salvage rates. Anatomic data was confirmed in all 17 patients incorporated into the Kaplan-Meier life tables. Log-rank analysis was used to compare 18 the primary patency rates of endovascular and open surgical interventions. P value of ≤0.05 was 19 considered to be statistically significant. All analyses were performed with SAS 9.4 (Cary, NC). 20

Informed consent was obtained with consent to be treated and all patients were de-identified. 21

This study was conducted under IRB approved protocol. 22

Twenty-seven patients experienced arterial thrombotic events that required vascular 3 management (figure 1). The average age was 65.0 ± 13.8 years old. Ten (37.0%) patients were 4 female. Ten (37.0%) patients were Caucasian, 5 (18.5%) were African American, 4 (14.8%) 5

were Hispanic, 3 (11.1%) were Asian, and in 5 (18.5%) ethnicity was unknown. Baseline 6 antiplatelet and anticoagulant medications included 4 (14.8%) patients on enoxaparin, 5 (18.5%) 7 on apixaban, 7 (25.9%) on aspirin, and 4 (14.8%) on clopidogrel (Supplemental Table I coronary artery disease, 14.8% had chronic obstructive pulmonary disease, 11.1% had 10 congestive heart failure, and 11.1% had chronic kidney disease. 25.9% of patients were obese, 11 and 44.4% were current or former smokers (Supplemental Table II) . (Table I) . were anticoagulated post-operatively. 5 patients were treated with subcutaneous anticoagulation 17 alone, 2 were treated with subcutaneous anticoagulation and antiplatelet therapy, 7 were treated 18 with oral anticoagulation alone, and 5 with oral anticoagulation and antiplatelet therapy. The one 19 patient who was not anticoagulated was treated with dual anti-platelet therapy. 20

Three-month follow-up was available in all 27 (100%) patients. Upon three-month 2 follow-up, 11 (40.7%) patients were deceased. Nine (81.8%) of the patients who expired did so 3 during their initial hospital stay. Causes of death included 1 (9.1%) cardiac arrest, 7 (63.6%) 4 cases of pneumonia, and 3 (27.3%) multisystem organ failures. Causes of death of the patients 5 who survived initial hospitalization but died within 3 months of their index intervention included 6 1 pneumonia and 1 multisystem organ failure. Four of the 7 patients treated conservatively were 7 deceased at 3 months. Nine (33.3%) patients required readmission, 8 (88.9%) of which were 8 unplanned (Table II) . Indications for readmission included hypoxia in 2 patients, critical limb 9 ischemia in 2 patients, CVA in 1 patient, cellulitis in 1 patient, CAD in 1 patient, wound 10 infection in 1 patient, and amputation stump infarction in 1 patient. The 3-month limb salvage 11 rate was 89.2% ± 7.2% (figure 2). Nineteen (70.4%) patients experienced 1 or more postoperative complications within 3-20 months of their index procedure. These included 9 (33.3%) patients with wound infections, 2 21 (7.4%) with DVT, 4 (14.8%) with acute kidney injuries, 3 (11.1%) major amputations, 2 (7.4%) 22 myocardial infarctions, 2 strokes (7.4%), 3 (11.1%) cases of pneumonia, 2 (7.4%) reintubations, 23 and 1 arterial occlusion (3.7%). Five (18.5%) patients experienced hemorrhagic complications, 1 which included 1 graft dehiscence and hemorrhage due to graft infection, 1 bleed from the 2 tracheostomy site, and 3 hematomas. Two (7.4%) patients experienced ischemic neuropathy 3 (Table II) . were deceased, all of whom were arterial patients. The patient who expired after 3 months was 8 initially discharged from the hospital and later died of multisystem organ failure. There were 9 9 total major lower extremity amputations in 7 (28.0%) patients at 6 months, 6 of which were 10 performed as the initial treatment. Kaplan-Meier analysis demonstrated the 6-month limb salvage 11 rate to be 89.2% ± 7.2% (figure 2). No patients required major lower extremity amputation 12 between 3-and 6-months. There were no open surgical revascularizations that lost patency between 3-and 6-months. In the 20 endovascular treatment group at 6 months, 1 of 2 percutaneous thrombectomies maintained 21 patency. 1 endovascular intervention lost patency between 3-and 6-months. 2 of 2 patients 22 treated conservatively experienced no progression of their symptoms. 23

In between 3-and 6-month follow-up, there was one additional hemorrhagic 1 complication which was a gastrointestinal bleed that occurred at 112 days post-op in a patient 2 that was anticoagulated with apixaban. No other complications were seen between 3-and 6-3 month follow-up (Table II) . 4

Average time from intervention to diagnosis of complication was 29.7 ± 22.2 days for 5 wound infections, 48.7 ± 42.0 days for hemorrhage, 59.0 ± 21.2 days for ischemic neuropathy, 6 7.5 ± 6.5 days for DVT, 2.8 ± 2.2 days for AKI, 16.0 ± 23.4 days for major amputations, 8.5 ± 7 10.6 for MI, 15.5 ± 20.5 days for CVA, 39.0 ± 44.2 days for pneumonia. The one arterial 8 occlusion occurred at 12 days. 9

Discussion 11 COVID-19 continues to infect thousands of people worldwide each day with an 12

increasing death count months after its initial discovery and presentation. 6 There are increasing 13 reports of thrombotic complications following COVID-19. Arterial thromboembolism has been 14 observed in ICU patients at a rate of 3.7%. 9 confirmed COVID-19 in March and April. 14 We found that 26 patients experienced an acute 19 arterial thrombotic event during this time period, giving a rough incidence rate of 0.4% of 20 COVID-19 patients. Thus, it is important that we improve our understanding of the thrombotic 21 sequelae of COVID-19 on the arterial and venous circulation to optimize management of 22 thrombotic events. Although multiple studies report immediate outcomes following thrombotic 23 events, there is limited follow-up data. To the authors' knowledge, this is the first study to report 1 3-month or 6-month outcomes following acute thrombotic events from COVID-19. 2

In New York City, the number of patients admitted with COVID-19 rapidly increased in 3

March 2020 and then quickly declined, and there were very few people hospitalized with 4 COVID-19 after May 2020. Thus, there were even fewer patients who experienced acute arterial 5 thrombotic events in the following months. As the number of patients with COVID-19 has 6 increased throughout the country, we expect the incidence of associated arterial thrombotic 7 events to likewise increase. 8

Hypertension was the most frequent patient comorbidity in this study. Few patients had 9

clinically evident underlying peripheral vascular disease. This suggests that peripheral vascular 10 disease was not the main driver of acute thrombotic events. It was not possible to definitively 11 establish whether the etiology of these events was in situ thrombosis or embolus from a remote 12 source in the majority of patients. Furthermore, the majority of patients with ALI did not have 13 severe COVID-19 infection, suggesting COVID-19 disease severity may not necessarily 14 correlate with risk of acute arterial thrombotic events. Thus, these acute arterial events may 15 develop via a separate mechanism. However, this finding may be biased by having a larger 16 number of patients hospitalized with moderate COVID-19 infection than with severe infection. 17

The majority of patients underwent a procedure of which was most commonly open 18 surgical intervention. The intervention rate in patients with acute thrombotic events in our series 19 is 74%. In thrombotic events seen in COVID-19 patients, the intervention rates have a wide 20 range in the literature. In Garg et al. series of patients, the intervention rate was 50%. 11 In a study 21 of 7 patients by Kashi et al. in France, only 2 patients underwent surgical intervention. 15 In our 22 study, the patients who were treated with heparin alone and did not receive any intervention had 23 critical COVID-19 illness and severity of presentation that precluded surgical revascularization. 1

The primary amputation rate in this study was 22.2% for major amputations and 7.4% for minor 2 amputations. This is higher than other reported rates in the literature. In Etkin et al. series of 49 3 patients, the primary amputation rate was 10%. 5 4

In our study, there was a high mortality rate of 40.7% at 3 months and 48.0% at 6 5 months, which appear to be greater than mortality rates of non-COVID patients with ALI. In 6

Taylor et al. study of 1000 consecutive revascularized limbs, they reported an overall 6-month 7 mortality rate of 14%. 16 Other studies have shown 6-month mortality rates of 12.3% and 8

16%. 17,18 9

The causes of mortality in our study included cardiac arrest, pneumonia and multi-system 10 organ failure. 75% of deaths occurred during the initial hospitalization and 25% occurred after 11 discharge. Thus, the highest risk for mortality is during the initial hospitalization. A recent study 12 Our study also found that 2 patients developed postoperative ischemic neuropathy. In one 1 patient, intervention was delayed by 14 days due to the COVID-19 pandemic, likely precipitating 2 this complication. The other patient experienced 7 days of lower extremity numbness and pain 3 before presenting to the hospital with acute limb ischemia. This highlights the risks of delayed 4 presentation and intervention that patients may face in the setting of the COVID-19 pandemic. 5

Early in the pandemic experience, endovascular approaches for the treatment of acute 6 thrombotic events appeared to have lower efficacy anecdotally, and therefore we preferred to use 7 an open surgical revascularization approach. This highlights the importance of this study in 8 providing more objective data to determine the optimal surgical management of patients with 9

acute thrombotic events associated with COVID-19. 10

This study showed an overall 72.2% 3-month primary patency rate, a 61.9% 6-month 11 primary patency rate, and major amputations in 28.0% of patients at 6-months. The majority of This study showed a 6-month limb salvage rate of 89.2%, which is similar to that of non-3 COVID-19 patients with ALI, as studies have shown 6-month limb salvage rates of 83% to 4 90%. [16] [17] [18] No patients with non-occlusive thrombosis who did not have clinically significant 5 ischemia were included in our study. It appears that lower extremity revascularization is effective 6 at preventing limb loss in patients with COVID-19 if the patient survives the initial illness 7 without major amputation. 8

Additionally, choice of anticoagulation postoperatively is important. Studies have shown 9 that patients will still have thrombotic events despite prophylactic anticoagulation. 27 In fact the 10 failure rate of prophylactic doses of LMWH has been shown to be 20% in patients with COVID-11 19 which is significantly higher than the 2.7% failure rate shown in randomized clinical trials in 12 critically ill, non-COVID patients. 2 Current guidelines state that all hospitalized patients with 13 COVID-19 should be treated with prophylactic anticoagulation, and that anticoagulant and 14 antiplatelet therapy should not be used to prevent arterial thromboses outside of the standard of 15 care for non-COVID patients. Interestingly, in our series, several patients developed thrombotic 16 events on anticoagulation. 18.5% of the patients in our series were on apixaban prior to 17 admission; and 14.8% were on prophylactic dose LMWH. Therefore, the lower patency rates are 18 likely related to an insufficient understanding of the mechanism of thrombosis in these patients 19

and also possibly to the severity of endothelial injury. 20

We present the largest series of follow-up on patients with thrombotic events in the 21 setting of COVID-19 to date. However, our study does have several limitations. Statistical 22 analysis was influenced by having a larger number of patients hospitalized with moderate 23 COVID-19 than severe COVID-19. Post-procedural follow-up imaging was not available in a 1 minority of patients. Furthermore, the type of revascularization performed was influenced by 2 patient presentation. Finally, this study only included patients for whom vascular surgery consult 3 was performed. 4 5

Patients with acute COVID-19 infections who experienced acute arterial thrombotic 7 events saw overall poor outcomes at three-and six-month follow up. In particular, these patients 8 saw a relatively lower patency rate, high complication rate, high mortality rate, and limb loss. 9

The major risk of adverse events appears to be during the initial hospitalization, and patients who 10 survive the hospitalization without a major amputation may have a prognosis similar to that 11 reported for patients with ALI not associated with COVID-19 infection. Table analysis showing limb salvage rates of 89.2% ± 7.2% at 3and 6-months, and number of patients at risk of limb loss at 0, 3, and 6 months. Table analysis showing 3-and 6-month primary patency rates of vascular interventions at 72.2% ± 10.6% and 61.9% ± 13.2% respectively for patients with acute thrombotic events associated with COVID-19 infection, with number of patients at risk of loss of primary patency at 0, 3, and 6 months. 

Incidence 13 of thrombotic complications in critically ill ICU patients with COVID-19

Acute limb 17 ischemia in patients with COVID-19 pneumonia

Acute Thrombotic Events as

Initial Presentation of Patients with COVID-19 infection

Intra-arterial thrombosis associated with COVID-19

Outcomes of Critically Ill Patients with COVID-19 Who Received Systemic Thrombolysis for 10

Presumed Pulmonary Embolism: an Observational Study 19

Severe arterial thrombosis 14 associated with Covid-19 infection

Determinants of functional outcome after revascularization for critical limb ischemia: an analysis 18 of 1000 consecutive vascular interventions

AMS INSIGHT--absorbable metal stent implantation for 16 treatment of below-the-knee critical limb ischemia: 6-month analysis

Rheolytic 20 thrombectomy in the management of acute and subacute limb-threatening ischemia

Long-term Outcome after Thrombolysis for Acute

Patients with COVID-19: Its Role in Thrombosis and Adverse Outcomes

Incidence of 17 venous thromboembolism in hospitalized patients with COVID-19

J o u r n a l P r e -p r o o f