Key Points
Question
Is prolonged-duration chemoprophylaxis associated with reductions in venous thromboembolism among high-risk patients with head and neck cancer undergoing oncologic surgery?
Findings
In this cohort study of 247 high-risk patients with head and neck cancer, prolonged-duration chemoprophylaxis was independently associated with reductions in venous thromboembolism but increases in nonfatal bleeding events.
Meaning
The study’s findings indicate that prolonged-duration chemoprophylaxis among patients with head and neck cancer undergoing oncologic procedures may be associated with reductions in perioperative venous thromboembolism; however, the associated increase in nonfatal bleeding events warrants careful consideration and further highlights the importance of determining an optimal duration of chemoprophylaxis among this distinct cohort.
Abstract
Importance
Venous thromboembolism (VTE) is associated with substantial morbidity and is the most common factor associated with preventable death among hospitalized patients. Data from otolaryngologic studies suggest that the risk of VTE may be underestimated among high-risk patients, particularly among those undergoing oncologic procedures. The incorporation of prolonged-duration chemoprophylaxis (PDC) into preventive therapy has been associated with substantial decreases in VTE incidence among patients undergoing oncologic surgery. However, bleeding remains a major concern among otolaryngologists, and substantial variation exists in the use of thromboprophylaxis.
Objective
To assess the association between PDC and VTE in high-risk patients with head and neck cancer undergoing oncologic procedures.
Design, Setting, and Participants
This retrospective cohort study identified 750 patients with biopsy-confirmed head and neck cancer and a Caprini risk score of 8 or higher who underwent inpatient oncologic surgery at a tertiary care referral center between January 1, 2014, and February 1, 2020. After exclusions, 247 patients were included in the study; patients were divided into 2 cohorts, traditional and PDC, based on the duration of prophylaxis. Univariate and multivariate analyses were performed to examine the development of VTE and bleeding-associated complications during the 30-day postoperative period. Data were analyzed from April 1 to April 30, 2020.
Exposures
PDC, defined as 7 or more postoperative days of chemoprophylaxis.
Main Outcomes and Measures
VTE and bleeding events during the 30-day postoperative period.
Results
Among 247 patients (mean [SD] age, 63.1 [11.1] years; 180 men [72.9%]) included in the study, 106 patients (42.9%) received traditional prophylaxis, and 141 patients (57.1%) received PDC. The incidence of VTE was 5 of 106 patients (4.7%) in the traditional cohort and 1 of 141 patients (0.7%) in the PDC cohort (odds ratio [OR], 0.15; 95% CI, 0.003-1.33). In the multivariate logistic regression analysis, PDC was independently associated with reductions in the risk of VTE (OR, 0.04; 95% CI, 0.001-0.46). The incidence of bleeding events was 1 of 106 patients (0.9%) in the traditional cohort and 6 of 141 patients (4.3%) in the PDC cohort (OR, 4.64; 95% CI, 0.55-217.00).
Conclusions and Relevance
The use of chemoprophylaxis for high-risk patients with head and neck cancer remains a high-priority topic. The results of this study suggest that PDC may be associated with reductions in VTE among this patient population. However, the associated increase in nonfatal bleeding events warrants careful consideration and further highlights the need to determine an optimal duration for chemoprophylaxis among this distinct cohort.
This cohort study examines the association between prolonged-duration chemoprophylaxis and the incidence of venous thromboembolism and bleeding events among high risk-patients with head and neck cancer.
Introduction
Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is often cited as the most preventable factor associated with mortality among hospitalized patients.1 Yet, 600 000 patients have VTE,2 and VTE is associated with 5% to 10% of all hospital-associated deaths each year in the US.3 Factors such as cancer and surgery increase this risk, with some studies reporting that VTE is the most common factor associated with death among postoperative patients with cancer.4 Despite treatment, VTE-associated mortality approaches 10%,5 and one-half of patients with VTE are likely to have long-term complications, such as postthrombotic syndrome, recurrent thromboembolism, pulmonary hypertension, and the associated risks of therapeutic anticoagulation.6
Aside from the health implications, the treatment of VTE is expensive and contributes substantially to the health care burden. Acute costs range from $12 000 to $15 000 per patient, but complications may increase this cost to $23 000 or more.7 With annual expenditures of $7 to $10 billion, VTE is considered a pay-for-performance measure by the Center for Medicare & Medicaid Services.7,8 As a consequence, hospital regulating agencies, such as the Joint Commission and the Agency for Healthcare Research and Quality, consider VTE prevention the most important strategy for improving patient safety.7
Risk Factors and Incidence of VTE
Surgical oncology patients are distinct in that they experience the full Virchow triad with prolonged operative times, direct endothelial trauma, and a cancer-associated prothrombotic state. Indeed, patients with cancer are 4 to 7 times more likely to have DVT or PE compared with individuals without cancer.9 For those undergoing major surgical procedures, the risk is increased 20-fold.10,11 Furthermore, data suggest that this risk remains high for 90 days after surgery.12
With several factors associated with the development of VTE, the identification of at-risk populations is challenging. The use of validated risk assessment models, such as the Caprini risk score, has largely mitigated this issue by assigning each risk factor a specific point value that is directly proportional to the relative risk of VTE.13 Since its conception, the Caprini risk score has been externally validated in general surgery, critical care surgery, endocrine surgery, foot and ankle surgery, vascular surgery, otolaryngologic surgery, and plastic and reconstructive surgery.14,15,16,17,18,19
Otolaryngologic patients have historically been considered low risk, with an estimated VTE incidence in the range of 0.1% to 2.4%.15,20,21,22 However, data from the past 10 years indicate that this risk has been underestimated, particularly in high-risk subgroups. For example, the incidence of postoperative VTE among patients with head and neck cancer (HNC) has been reported to be as high as 13% in the absence of postoperative chemoprophylaxis.10 When stratified by Caprini risk score,14,23 patients with a score higher than 8 have a VTE incidence in the range of 14.5% to 33.0%.15,24,25,26 A Caprini risk score higher than 8 is thought to generate a 20-fold increase in VTE risk.15,17
Current Guidelines for VTE Prophylaxis
Since 1986, the American College of Chest Physicians has published recommendations on thrombosis prevention, emphasizing risk reduction while minimizing pharmacologic sequela.27 For surgical patients, recommendations are based on reporting of predicted risk of symptomatic VTE using patient- and procedure-specific risk assessment models. For those with cancer, the American College of Chest Physicians currently recommends chemoprophylaxis with low-molecular-weight heparin (LMWH) for 7 to 10 days after surgery. This regimen is also supported by the American Society of Clinical Oncology,28 the National Comprehensive Cancer Network,4,29 and the American Society of Plastic Surgeons.30 In certain high-risk populations, extended-duration chemoprophylaxis with 4 weeks of LMWH is recommended. This recommendation includes patients undergoing abdominal or pelvic surgery for cancer, those with advanced-stage disease, those older than 60 years, those undergoing oncologic procedures lasting 2 or more hours, and those with limited postoperative mobility for 4 or more days.4,31,32
Notably, there is no consensus regarding patients with HNC. Instead, preventive therapy for VTE relies primarily on consultant preference and/or the use of indirect evidence from similar high-risk fields, which is likely the consequence of a paucity of data from this population. Indeed, previous studies are limited by heterogenous study populations and inconsistent documentation of chemoprophylaxis duration. Moreover, variations in training habits, lack of external validation, and persistent concerns regarding complications, such as neck or free-flap hematomas, are not inconsequential. As such, the incidence of VTE among patients with HNC remains high, with considerable impact for morbidity and mortality.
The purpose of this study was to evaluate the association between prolonged-duration chemoprophylaxis (PDC) and VTE among high-risk patients with HNC undergoing oncologic procedures. To our knowledge, this study is the first to evaluate the use of PDC in this population.
Methods
Patient Selection
We reviewed all medical records of patients 18 years and older who underwent inpatient surgery (defined as a hospital stay of ≥48 hours) by a primary surgeon of the otolaryngology service at a tertiary care referral center between January 1, 2014, and February 1, 2020. Patients with biopsy-confirmed HNC and a Caprini risk score of 8 or higher who underwent oncologic surgery for 2 or more hours were identified. The study was approved by the institutional review board of the State University of New York Upstate Medical University; because the study was retrospective, it was deemed exempt from informed consent according to federal guidelines. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.
In 2014, the State University of New York Upstate Medical University implemented all patient safety indicators recommended by the Agency for Healthcare Research and Quality, and the initiation of thromboprophylaxis was based on institute-specific guidelines, which recommended the use of sequential compression devices and/or LMWH or unfractionated heparin therapy for high-risk surgical inpatients. In 2017, a mandatory VTE screening tool was integrated into the institution’s electronic medical records system, with a corresponding order set based on the patient-specific Caprini risk score.31 In accordance with updated institutional protocols and current guidelines from the American College of Chest Physicians, all patients with high VTE risk (Caprini risk score, 5-8) and severe VTE risk (Caprini risk score ≥9) are recommended to receive either 7 to 10 days or 30 days of postoperative chemoprophylaxis, respectively. Before 2017, the use of chemoprophylaxis was limited to the inpatient hospital stay and was independent of Caprini risk score.
The study population was divided into 2 cohorts based on the duration of prophylaxis to reflect current hospital and professional guidelines.4,27,28,29,30 Patients in the PDC cohort received 7 or more days of postoperative chemoprophylaxis (30-40 mg of LMWH per day or 5000 U of unfractionated heparin 3 times per day), which they may or may not have continued to receive after hospital discharge depending on updated institutional recommendations and/or the individual length of stay. Patients were then compared with a traditional cohort based on historical institutional protocols, which limited thromboprophylaxis to inpatient hospital stay. Therefore, patients were included in the traditional cohort if the maximum duration of thromboprophylaxis was 6 days or less and if thromboprophylaxis was discontinued before hospital discharge. For all patients, prophylaxis was initiated on postoperative day 1.
Patients were excluded from the study if they had outpatient surgery, benign tumors, thyroid and parathyroid tumors, active gastrointestinal bleeding, allergy to heparin, no documented thromboprophylaxis, history of heparin-induced thrombocytopenia, history of coagulopathy or thrombophilia, and/or use of therapeutic anticoagulation treatment and/or glycoprotein IIb/IIIa inhibitors at the time of surgery. Patients who were taking aspirin (81-325 mg) and patients who initiated therapeutic anticoagulation during the study period were not excluded from the final analysis.
Data Collection
Medical records were reviewed for age, sex, race, diagnosis, primary tumor location, smoking status, length of stay, operative time (in hours), and use of concurrent aspirin, and whether patients underwent free tissue transfer (FTT). The type, dosage, and duration (in days) of prophylaxis were recorded. The Caprini risk score was manually calculated by 2 investigators (K.E.T. and L.B.) for each participant according to current institutional protocols.14
All thromboembolic events were diagnosed with venous duplex ultrasonography and/or computed tomography angiography. Patients with confirmed DVT or PE within the 30-day postoperative period were recorded. Superficial vein thrombosis was not considered a thromboembolic event, as they are not reported to be associated with PE.
All bleeding events were identified and recorded if they were grade 1 or higher on the Memorial Sloan Kettering Surgical Secondary Events scale (grade range, 1-5, with higher grades indicating more severe events) during the 30-day postoperative period.33 Blood transfusions for intraoperative hemorrhage or anemia associated with chronic disease were not recorded as bleeding events. Bleeding and VTE events occurring before administration of chemoprophylaxis were not considered adverse events, as they could not be associated with pharmacologic intervention. Because previous findings have suggested a higher incidence of both VTE and bleeding complications in patients undergoing free flap reconstruction,25,34 we conducted separate univariate analyses of these 30-day outcomes in both the traditional and PDC cohorts for those who underwent FTT vs those who underwent all other procedures.
Statistical Analysis
Variables were selected a priori. For categorical variables, univariate analysis was performed using a paired 2-tailed Fisher exact test; results were reported as numbers and percentages with odds ratios (ORs) and 95% CIs. For continuous variables, a linear regression analysis was performed, and results were reported as numbers, means, and SDs; effect sizes were expressed η2 with 95% CIs.
Multivariate logistic regression was performed for each outcome of interest using preselected variables known to be associated with each respective outcome. For the VTE analysis, these variables included age, Caprini risk score, operative time, cohort, and whether participants underwent FTT. For the bleeding analysis, variables included smoking status, Caprini risk score, cohort, use of concurrent aspirin or therapeutic anticoagulation, and whether participants underwent FTT. Results were reported as effect sizes with ORs and 95% CIs. Statistical analysis was performed using the 2017 version of R software (R Foundation for Statistical Computing). Data were analyzed from April 1 to April 30, 2020.
Results
A total of 247 patients (mean [SD] age, 63.1 [11.1] years; 180 men [72.9%]) with HNC and a Caprini risk score of 8 or higher who underwent inpatient surgery lasting 2 or more hours between January 1, 2014, and February 1, 2020, were included in the analysis (Table 1; Figure). Of those, 141 patients (57.1%) received PDC for a mean (SD) duration of 16.3 (10.1) days, and 106 patients (42.9%) received traditional prophylaxis for a mean duration of 2.8 (1.7) days. Cohorts were well matched in age, sex, race, smoking status, and Caprini risk score. However, patients in the PDC cohort compared with the traditional cohort were more likely to have squamous cell carcinoma (130 of 141 patients [92.2%] vs 85 of 106 patients [80.2%], respectively), longer operative times (mean [SD], 10.4 [4.2] hours vs 6.5 [2.9] hours), prolonged length of stay (mean [SD], 11.3 [6.5] days vs 4.1 [4.3] days), and to receive concurrent aspirin (92 of 141 patients [65.2%] vs 36 of 106 patients [34.0%]) and undergo free flap reconstruction (62 of 141 patients [44.0%] vs 3 of 106 patients [2.8%]) (Table 1).
Table 1. Characteristics of Participants.
| Characteristic | Total | Traditional cohort | PDC cohort | Effect size, η2 (95% CI) | Odds ratio (95% CI) |
|---|---|---|---|---|---|
| Total participants, No. | 247 | 106 | 141 | NA | NA |
| Numerical variables, mean (SD) | |||||
| Age, y | 63.1 (11.1) | 63.7 (11.4) | 62.7 (10.8) | 0.002 (0-0.029) | NA |
| Caprini risk score | 10.6 (1.3) | 10.5 (1.5) | 10.6 (1.2) | 0.001 (0-0.024) | NA |
| Length of hospital stay, d | 8.2 (6.7) | 4.1 (4.3) | 11.3 (6.5) | 0.286 (0.195-0.370) | NA |
| Operative time, h | 8.7 (4.2) | 6.5 (2.9) | 10.4 (4.2) | 0.218 (0.133-0.302) | NA |
| Duration of chemoprophylaxis, d | 10.5 (10.2) | 2.8 (1.7) | 16.3 (10.1) | 0.430 (0.340-0.505) | NA |
| Categorical variables, No. (%) | |||||
| Sex | |||||
| Male | 180 (72.9) | 78 (73.6) | 102 (72.3) | NA | 1.06 (0.58-1.96) |
| Female | 67 (27.1) | 28 (26.4) | 39 (27.7) | ||
| Race | |||||
| White | 233 (94.3) | 100 (94.3) | 133 (94.3) | NAa | NA |
| Black or African American | 5 (2.0) | 1 (0.9) | 4 (2.8) | ||
| Other | 8 (3.2) | 5 (4.7) | 3 (2.1) | ||
| Unknown | 1 (0.4) | 0 | 1 (0.7) | ||
| Diagnosis | |||||
| SCC | 215 (87.0) | 85 (80.2) | 130 (92.2) | NA | 2.91 (1.26-7.04) |
| Other | 32 (13.0) | 21 (19.8) | 11 (7.8) | ||
| Location | |||||
| Oral cavity | 111 (44.9) | 34 (32.1) | 77 (54.6) | NAa | NA |
| Oropharynx | 40 (16.2) | 23 (21.7) | 17 (12.1) | ||
| Larynx | 38 (15.4) | 7 (6.6) | 31 (22.0) | ||
| Hypopharynx | 5 (2.0) | 0 | 5 (3.5) | ||
| Sinonasal | 3 (1.2) | 1 (0.9) | 2 (1.4) | ||
| Cutaneous | 27 (10.9) | 21 (19.8) | 6 (4.3) | ||
| Other | 23 (9.3) | 20 (18.9) | 3 (2.1) | ||
| Current smoker | |||||
| Yes | 69 (27.9) | 29 (27.4) | 40 (28.4) | NA | 1.05 (0.58-1.93) |
| No | 178 (72.1) | 77 (72.6) | 101 (71.6) | ||
| Received FF surgery | |||||
| Yes | 65 (26.3) | 3 (2.8) | 62 (44.0) | NA | 26.7 (8.22-137.60) |
| No | 182 (73.7) | 103 (97.2) | 79 (56.0) | ||
| VTE event | |||||
| Yes | 6 (2.4) | 5 (4.7) | 1 (0.7) | NA | 0.15 (0.003-1.33) |
| No | 241 (97.6) | 101 (95.3) | 140 (99.3) | ||
| Bleeding event | |||||
| Yes | 7 (2.8) | 1 (0.9) | 6 (4.3) | NA | 4.64 (0.55-217.00) |
| No | 240 (97.2) | 105 (99.1) | 135 (95.7) | ||
| Received aspirin | |||||
| Yes | 128 (51.8) | 36 (34.0) | 92 (65.2) | NA | 3.63 (2.08-6.43) |
| No | 119 (48.2) | 70 (66.0) | 49 (34.8) | ||
| Received therapeutic anticoagulation | |||||
| Yes | 6 (2.4) | 5 (4.7) | 1 (0.7) | NA | 0.15 (0.003-1.33) |
| No | 241 (97.6) | 101 (95.3) | 140 (99.3) |
Abbreviations: FF, free flap; NA, not applicable; PDC, prolonged-duration chemoprophylaxis; SCC, squamous cell carcinoma; VTE, venous thromboembolism.
Effect sizes were not calculated for categorical variables with more than 2 categories.
Figure. Study Flowchart.
LMWH indicates low-molecular-weight heparin; PDC, prolonged-duration chemoprophylaxis; SCD, sequential compression device; and UFH, unfractionated heparin.
The overall incidence of VTE in the study population was 6 of 247 patients (2.4%; 2 patients [0.8%] with DVT and 4 patients [1.6%] with PE). Of those with VTE, 2 patients died of VTE-associated complications, both of whom were in the traditional cohort (Table 2). In the univariate analysis, the incidence of VTE was 5 of 106 patients (4.7%) in the traditional cohort and 1 of 141 patients (0.7%) in the PDC cohort, which reflected an almost 7-fold reduction in VTE events (OR, 0.15; 95% CI, 0.003-1.33). After accounting for age, Caprini risk score, smoking status, operative time, and free flap status on the multivariate analysis, PDC was independently associated with a 28-fold reduction (OR, 0.04; 95% CI, 0.001-0.46) in VTE events (Table 3). With each cumulative day of unfractionated heparin or LMWH, the VTE risk decreased from approximately 5% at postoperative day 0 (before administration of prophylactic anticoagulation) to less than 1% after 15 days of consecutive chemoprophylaxis (OR, 0.85; 95% CI, 0.68-1.05) (eFigure 1 in the Supplement).
Table 2. Complications Among Participants With Venous Thromboembolism.
| Patient No. | Cohort | Received FF surgery | Diagnosis date, postoperative day | VTE description | Presentation | Treatment | Complication |
|---|---|---|---|---|---|---|---|
| 151 | Traditional | No | 2 | Unilateral segmental PE | Increased O2 requirements | Enoxaparin for 3 mo | Pharyngocutaneous fistula; chronic aspiration; ARDS; death |
| 226 | Traditional | Yes | 3 | Bilateral lobar PEs | Chest pain; shortness of breath; increased O2 requirements | Enoxaparin for 3 mo | Multiple hematomas requiring exploration; IVC filter |
| 153 | Traditional | No | 7 | Unilateral occlusive DVT | Lower extremity pain | Warfarin for 3 mo | None |
| 213 | Traditional | No | 8 | Unilateral lobar PE | Incidental finding on staging CT | Rivaroxaban for 6 mo | None |
| 183 | Traditional | No | 12 | Bilateral submassive PE | Syncope and tachypnea at home | Catheter-directed thrombectomy | PEA arrest; death |
| 16 | PDC | Yes | 14 | Unilateral proximal DVT | Leg swelling | Apixaban for 3 mo | None |
Abbreviations: ARDS, acute respiratory distress syndrome; CT, computed tomography; DVT, deep vein thrombosis; FF, free flap; IVC, inferior vena cava; O2, oxygen; PDC, prolonged-duration chemoprophylaxis; PE, pulmonary embolism; PEA, pulseless electrical activity; VTE, venous thromboembolism.
Table 3. Multivariate Logistic Regression Analysis for Risks of Venous Thromboembolism and Bleeding Events.
| Variable | Odds ratio (95% CI) |
|---|---|
| Venous thromboembolism | |
| Age | 1.04 (0.95-1.14) |
| Cohort (PDC) | 0.04 (0.001-0.46) |
| Caprini risk score | 1.25 (0.59-2.57) |
| Current smoker | 2.33 (0.27-17.80) |
| Operative time, h | 1.04 (0.70-1.45) |
| Received FF surgery | 8.17 (0.39-289.00) |
| Bleeding | |
| Cohort (PDC) | 3.87 (0.32-133.00) |
| Caprini risk score | 1.12 (0.59-2.02) |
| Received aspirin | 0.42 (0.03-5.57) |
| Received therapeutic anticoagulation | 12.30 (0.43-360.00) |
| Received FF surgery | 7.85 (0.78-134.00) |
Abbreviations: FF, free flap; PDC, prolonged-duration chemoprophylaxis.
The overall incidence of bleeding complications in the study population was 7 of 247 patients (2.8%). No patients died or experienced life-threatening complications (Table 4). In the univariate analysis, the incidence of bleeding was 1 of 106 patients (0.9%) in the traditional cohort and 6 of 141 patients (4.3%) in the PDC cohort (OR, 4.64; 95% CI, 0.55-217.00). Of the 7 patients with bleeding events, 5 patients (71.4%) were concurrently receiving aspirin for preexisting conditions or for its benefits as antiplatelet therapy in patients undergoing FTT. Among the total study population, 128 of 247 patients (51.8%) received postoperative aspirin (36 of 106 patients [34.0%] in the traditional cohort vs 92 of 141 patients [65.2%] in the PDC cohort; OR, 3.63; 95% CI, 2.08-6.43). However, when controlling for aspirin, therapeutic anticoagulation, Caprini risk score, cohort, and free flap status in the multivariate logistic regression analysis, none of these factors were independently associated with bleeding events (Table 3).
Table 4. Complications Among Participants With Bleeding Events.
| Patient No. | Cohort | Received FF surgery | Diagnosis date, postoperative day | Received aspirin or therapeutic anticoagulation therapy | Complication |
|---|---|---|---|---|---|
| 28 | PDC | No | 3 | Aspirin | Incisional bleeding resolved at bedside |
| 63 | PDC | No | 4 | No | Oropharyngeal hemorrhage requiring embolization of external carotid branch after TORS |
| 102 | PDC | Yes | 5 | Aspirin | Flap congestion with small hematoma requiring exploration; flap intact |
| 15 | PDC | Yes | 5 | Aspirin | Hematoma with flap dehiscence and failure |
| 27 | PDC | Yes | 6 | Aspirin | Hematoma; flap failure |
| 266 | PDC | Yes | 2 | No | Primary free flap failure (postoperative day 0); expanding neck hematoma (postoperative day 2) |
| 226 | Traditional | Yes | 14 | Aspirin; therapeutic LMWH for VTE | Multiple hematomas requiring exploration and IVC filter; flap intact |
Abbreviations: FF, free flap; IVC, inferior vena cava; LMWH, low-molecular-weight heparin; PDC, prolonged-duration chemoprophylaxis; TORS, transoral robotic surgery; VTE, venous thromboembolism.
Among the 141 patients who received PDC, 62 patients (44.0%) underwent FTT compared with 3 of the 106 patients (2.8%) who received traditional prophylactic anticoagulation (OR, 26.7; 95% CI, 8.22-137.60). The overall incidence of VTE and bleeding events among the 65 patients who underwent FTT was 2 patients (3.1%) and 5 patients (7.7%), respectively. Results of the univariate analysis for VTE and bleeding outcomes in patients who underwent FTT are reported in the eTable in the Supplement.
Discussion
As reported in previous cohort studies,24,34,35 patients with HNC share several key factors making them more likely to have high Caprini risk scores and, consequently, a high incidence of VTE. Indeed, the current study population suggests an estimated Caprini risk score of 9 with a mean age older than 60 years, operative time greater than 6 hours, and active cancer (eFigure 2 in the Supplement). Nonetheless, pharmacologic prophylaxis remains inadequately studied in otolaryngology, and recommendations have been difficult to formulate given the lack of evidence-based data and variable adherence among head and neck surgeons. Randomized clinical trials from similar high-risk cohorts have reported a substantial reduction in VTE with PDC.32,36,37 To our knowledge, this study is the first to evaluate PDC in high-risk patients with HNC.
VTE Events
Compared with traditional anticoagulation, PDC was associated with an almost 7-fold reduction in VTE incidence in the univariate analysis. In the multivariate logistic regression analysis, PDC remained independently associated with reduced VTE events when we accounted for age, Caprini risk score, smoking status, operative time, and free flap status. Moreover, each cumulative day of chemoprophylaxis was associated with further reduction in the risk of VTE in the univariate analysis. The VTE risk decreased from approximately 5% at day 0 to less than 1% at day 15 and suggests that duration may be protective, independent of the presence of unfractionated heparin or LMWH (eFigure 1 in the Supplement).
Notably, the observed VTE incidence for the study population (2.4%) and for both the traditional (4.7%) and PDC (0.7%) cohorts were lower than expected compared with the VTE incidence of 10.7% to 13.2% observed in previous studies of patients with Caprini risk scores of 8 or higher in whom traditional prophylaxis was used.25,35 This finding may be associated with the mean duration of chemoprophylaxis for the overall study population, which was 10.5 days. However, previous studies did not specify duration of prophylaxis when stratifying high-risk populations, and we cannot exclude the possibility of a naturally lower incidence among participants in the present study.25
The lower VTE incidence observed in patients receiving PDC is unlikely to be associated with cohort differences or baseline VTE risk, as the mean Caprini risk scores for the traditional and PDC cohorts were 10.5 and 10.6, respectively, and was not associated with VTE in the multivariate analysis. Longer operative times, prolonged length of stay, and higher rates of FTT in the PDC cohort suggest the opposite and further substantiate our findings from the multivariate analysis. Moreover, the relative risk reduction in participants with nonfatal symptomatic VTE who received PDC was 72%, which is similar to the 76% reduction expected to occur with 4 weeks of chemoprophylaxis compared with 6 to 10 days of chemoprophylaxis in high-risk general surgery patients.31,32
In addition, most DVT and PE events (67%) occurred on or after postoperative day 7, which is consistent with previous findings indicating that VTE risk is not limited to hospitalization and cannot reliably be prevented with early ambulation or inpatient chemoprophylaxis in high-risk patients.12
Bleeding Events
Bleeding risk is well-documented with anticoagulation and presents a major concern. In plastic and reconstructive surgery, the baseline risk of postoperative hematoma is 0.5% to 1.8% in the absence of chemoprophylaxis.38,39,40 In high-risk patients with HNC, particularly those receiving routine chemoprophylaxis, the true risk is unknown given the heterogeneity of previous study populations. In the present study, PDC was associated with a 4-fold increase in perioperative bleeding events. However, this increase was not independently associated with increases in bleeding events in the multivariate analysis, and the observed incidence of 4.3% is comparable to the 3.5% incidence among otolaryngologic inpatients receiving chemoprophylaxis that was reported by Bahl et al.25 Notably, 6 of 7 bleeding events (85.7%) occurred on postoperative day 6 or earlier, which indicates that most patients received fewer than 7 days of chemoprophylaxis at the time of hemorrhage. Although the reason for this discrepancy is unclear, it suggests that the observed increase may be associated with underlying cohort differences rather than treatment duration.
Notably, this study included minor bleeding complications, which is in contrast to previous studies.25,41 The incidence of bleeding may therefore be overestimated in this study. Nonetheless, no patients died or experienced life-threatening hemorrhages from complications of bleeding (Table 4). The same cannot be said of VTE complications (Table 2). Thus, 1 bleeding event cannot be considered equivalent to 1 VTE event given the disproportionate increases in morbidity and mortality associated with the latter.
More than 50% of patients received either concurrent aspirin for preexisting conditions or antiplatelet therapy associated with FTT. Although the multivariate analysis did not reveal increased bleeding risk associated with this combination, this lack of increase may be due to insufficient study power, given 71% of bleeding events occurred in those receiving concurrent antiplatelet therapy. Indeed, previous studies have reported that antiplatelet therapy is associated with an increased risk of bleeding in patients receiving chemoprophylaxis.25,42 Therefore, a preoperative discussion with the patient’s cardiologist or primary care physician is important to determine the necessity of continuing antiplatelet therapy during the perioperative period, particularly in light of the new American Heart Association guidelines.43
Microvascular Free Tissue Transfer
Patients undergoing free flap reconstruction often have higher Caprini scores and disproportionately higher risk of VTE, with an incidence of up to 35.3% without routine chemoprophylaxis.25 The overall VTE incidence for patients who underwent microvascular FTT was 3.1%. Because of our relatively small sample, there is a large amount of imprecision around the estimate of 3.1% for VTE events among patients who underwent microvascular FTT. Given the sample of 65 patients who underwent FTT, the data are consistent with an incidence as high as 10.6%, which has been reported in previous studies.25,34 Because all participants had Caprini risk scores of 8 or higher and free flap surgery was not independently associated with VTE, this incidence may reflect the benefits of PDC, given that 95% of patients who underwent free flap surgery received 7 or more days of chemoprophylaxis, with a mean duration of 16 days.
Although the antithrombotic outcomes of chemoprophylaxis are beneficial in reducing anastomotic thrombi in patients undergoing FTT, they are associated with increases in the risk of hematoma.44 In the present study, the incidence of bleeding complications in patients undergoing FTT was 7.7%. Given the sample size, the true incidence of bleeding complications could be as low as 3% and as high as 18%. Moreover, 95% of those undergoing FTT received PDC; therefore, we cannot reliably evaluate the true risk of bleeding events in comparison with those who received traditional prophylaxis. In addition, 95% of participants received concurrent aspirin, which is routinely given postoperatively for 30 days at our institution. This combination may explain the higher incidence of bleeding in FTT patients when compared with historical rates of 5.3% without chemoprophylaxis.45 Still, it is lower than the 11.9% rate observed in free flap patients receiving traditional chemoprophylaxis reported by Bahl et al.25
Limitations
This study has several limitations. It is limited by a small sample owing to strict inclusion criteria and a lower volume of patients with HNC at the study institution. A prestudy power calculation was not performed; based on the actual sample size, additional studies may be necessary to make more definitive conclusions, as many of the estimates are imprecise. Moreover, we present a single institution experience, which may render generalization difficult. This difficulty is particularly relevant regarding microvascular reconstruction, in which our limited patient population made it difficult to compare outcomes. Additionally, the true incidence of VTE may be underreported given the 30-day study period, as previous evidence suggests a sustained risk of up to 12 weeks.12
This study is further limited by its retrospective nature. Although adherence was recorded during hospitalization, we were not able to reliably confirm this at discharge. Moreover, there is a potential chronology bias, as cohorts were assigned retrospectively based on the duration of chemoprophylaxis. For example, hospital length of stay previously determined duration of chemoprophylaxis, such that a prolonged length of stay may have resulted in 7 or more days of chemoprophylaxis for patients presenting before 2017. Therefore, a duration cutoff of 7 or more days was used for inclusion in the PDC cohort because the duration of chemoprophylaxis has been shown to be the most effective factor associated with VTE prevention.4,27,28,29,30
Conclusions
The use of chemoprophylaxis in otolaryngology remains a high priority and an often-disputed topic. Nevertheless, it remains clear that, when postoperative VTE occurs, the consequences are substantial, long lasting, and potentially fatal. Patients with HNC represent a medically complex, high-risk subgroup of otolaryngologic patients. Caprini risk score validation has facilitated the identification of at-risk populations and represents an opportunity for intervention in these patients.
Despite the lower incidence of VTE observed in this study, our findings suggest that PDC with unfractionated heparin or LMWH for 7 or more days in high-risk patients with HNC undergoing oncologic procedures may be associated with reductions in perioperative VTE. However, it should be noted that chemoprophylaxis was associated with an increase in nonfatal bleeding events that may be independent of treatment duration. Therefore, in patients with a higher risk of bleeding, such as those undergoing FTT, the use of chemoprophylaxis warrants careful consideration, as complications such as flap failure can produce substantial harm. Although prospective clinical trials are necessary to validate our findings, this study highlights the importance of VTE prevention and further emphasizes the need to define the optimal duration of chemoprophylaxis in high-risk patients with HNC undergoing oncologic procedures.
eFigure 1. Logistic Regression Analysis Plotted on a Linear Model Showing Progressive Reduction in Unadjusted Risk of Venous Thromboembolism With Increasing Duration of Chemoprophylaxis
eFigure 2. Modified Institutional-Specific Caprini Risk Assessment Tool Reflecting Risk Factors for Venous Thromboembolism Among the Current Study Population Based on Mean Age, Operative Time, and Active Cancer Diagnosis
eTable. Free Tissue Transfer vs All Others
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eFigure 1. Logistic Regression Analysis Plotted on a Linear Model Showing Progressive Reduction in Unadjusted Risk of Venous Thromboembolism With Increasing Duration of Chemoprophylaxis
eFigure 2. Modified Institutional-Specific Caprini Risk Assessment Tool Reflecting Risk Factors for Venous Thromboembolism Among the Current Study Population Based on Mean Age, Operative Time, and Active Cancer Diagnosis
eTable. Free Tissue Transfer vs All Others