Significant Variability in Postoperative Thromboprophylaxis in Cushing's Disease Patients: A Survey of the North American Skull Base Society and the AANS/CNS Joint Tumor Section

Abstract

Introduction  Cushing's disease (CD) is associated with hypercoagulability which is associated with an increased risk of venous thromboembolic events (VTEs) perioperatively. This risk persists even after successful transsphenoidal surgery (TSS). However, there are no current guidelines for pharmacologic thromboprophylaxis in this patient population.

Objective  Characterize existing thromboprophylaxis management practices in patients undergoing TSS for CD.

Methods  An anonymous RedCap survey comprised of questions about perioperative thromboprophylaxis in CD patients was distributed via the American Association of Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) Joint Tumor Section and the North American Skull Base Society (NASBS) email lists.

Results  The survey was distributed to 554 members of the AANS/CNS Joint Tumor Section and 1,094 members of NASBS asking that members who surgically treat CD respond. Sixty responses (3.0% response rate) were received. Fifty-two (86.7%) respondents are involved in the postoperative management of CD patients. Thirty-six (69.2%) treat all patients with postoperative VTE chemoprophylaxis, 8 (15.4%) treat some patients, while 8 (15.4%) do not use chemoprophylaxis. Preferred chemoprophylaxis varies as 26 (59.1%) administer low molecular weight heparin, 14 (31.8%) give unfractionated heparin, 1 (2.3%) give direct oral anticoagulants, and 3 (6.8%) give aspirin. Most (28, 53.8%) of the respondents perceive the VTE risk in this patient population to be 0 to 5%, 16 (30.8%) perceive the risk to be 6 to 10%, and 8 (15.4%) perceive it to be 11 to 20%.

Conclusion  There is great variability in VTE detection and postoperative prevention practice patterns in CD patients. This study highlights the need for prospective studies to clarify optimal pharmacologic chemoprophylaxis strategies and duration in this patient population.

Introduction

Although incompletely understood, there is an association between Cushing's syndrome (CS) and hypercoagulability, which can result in significant morbidity and mortality due to venous thromboembolic and cardiovascular events. ^{1 2} In patients with Cushing's disease (CD), this risk has been reported to persist even after hormonal remission is achieved. Thus, patients with CD undergoing transsphenoidal surgery (TSS) are at risk of venous thromboembolic events (VTEs) in the perioperative period. ^{3 4}

There are no current guidelines for chemoprophylaxis in this unique patient population. There is retrospective evidence suggesting the utility of low molecular weight heparin in this population, but there is no high-quality evidence available supporting a specific chemoprophylaxis strategy for CD patients.

Development of evidence-based guidelines for this population is hindered by the low incidence of CD. The goal of this study is to assess current approaches to VTE screening and pharmacologic thromboprophylaxis in patients with CD undergoing TSS as a first step in developing an evidence-based management strategy for VTE in this population.

Methods

An anonymous online survey was created using RedCap (Vanderbilt University, 2023). A copy of survey questions is presented in the Supplemental Material . Questions about what characteristics would prompt pre- or postoperative screening or perioperative chemoprophylaxis were shown only to those respondents who selected “only in some patients” as their response to the specific question. This survey was distributed via email to members of the American Association of Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) Joint Tumor Section, as well as the North American Skull Base Society (NASBS), asking those that surgically treat CD to respond. Respondents were first asked: “are you involved in the postoperative management of patients who undergo surgery for CD?” If they responded “no” or if survey responses were incomplete, they were excluded from the analysis. Descriptive statistical analysis was conducted on anonymous survey responses using RedCap. Fisher's exact text to compare preoperative and postoperative screening practices and use of chemoprophylaxis between surgeons in academic and nonacademic practice settings and between surgeons practicing within and outside of the United States was performed in JMP (Version 16.2.0, SAS Institute Inc., Cary, North Carolina, United States, 1989–2021). The study was approved by our Institutional Review Board, and informed consent was provided in the form of an information sheet at the start of the survey.

Results

The survey was distributed to members of the AANS/CNS Joint Tumor Section (of which 554 are attending neurosurgeons), as well as 1,094 members on the NASBS mailing list (the number of attending neurosurgeons on this mailing list is unknown), asking for responses from those members who surgically treat CD. Although the survey verbiage was directed toward physicians at the attending level, there are members of NASBS and the AANS/CNS Tumor Section at the fellow, resident, and advanced practice practitioner level, and it is possible that some may have completed the survey. Sixty-one total responses were received, of which 60 were complete (3% response rate). Of those, 52 respondents were involved in the postoperative management of patients with CD and were included in further analysis.

Demographic information is presented in Table 1 . All respondents were neurosurgeons. Most practice within an academic center (82.7%) located in North America (81.0%).

Table 1. Demographic characteristics.

Characteristic	N (%)
Region of practice
North America	42 (81.0)
Central/South America	6 (11.5)
Europe	3 (5.8)
Asia	1 (1.9)
Practice setting
Academic	43 (82.7)
Private	12 (23.1)
Public	5 (9.6)
Military	1 (1.9)
CD surgeries performed annually by respondent
0–5	21 (40.4)
6–10	12 (23.1)
11 or more	19 (36.5)

Abbreviation: CD, Cushing's disease.

Four (7.7%) respondents perform preoperative screening (e.g., deep vein thrombosis [DVT] ultrasound) in all patients undergoing surgery, 7 (13.5%) perform preoperative screening in some patients undergoing surgery, 36 (69.2%) did not screen patients preoperatively, and 5 (9.6%) do not manage this aspect of their care ( Fig. 1A ). Among respondents who screen some patients, the following characteristics prompt screening: history of VTE, older age, elevated body mass index (BMI), history of cancer, history of diabetes, and smoking. The relative frequency of these characteristics is shown in Table 2 .

Fig. 1.

Proportion of respondents' replies to: ( A ) Do you perform radiographic screening (e.g., deep vein thrombosis [DVT] ultrasound of the legs) PREoperatively for patients undergoing pituitary surgery for Cushing's disease? ( B ) Do you perform radiographic screening (e.g., DVT ultrasound of the legs) POSToperatively for patients undergoing pituitary surgery for Cushing's disease? ( C ) Do you use pharmacologic thromboprophylaxis in your patients undergoing pituitary surgery for Cushing's disease?

Table 2. Characteristics prompting pre operative and post operative radiographic screening (e.g., DVT ultrasound) and perioperative chemoprophylaxis for VTE .

	Preoperative screening	Postoperative screening	Perioperative chemoprophylaxis
Characteristic	n (%)	n (%)	n (%)
History of VTE	7 (100)	11 (91.7)	8 (100)
Older age	3 (42.9)	6 (50.0)	3 (37.5)
Female gender	0	1 (8.3)	1 (12.5)
Elevated BMI	3 (42.9)	7 (58.3)	3 (37.5)
History of cancer	2 (28.6)	5 (41.7)	3 (37.5)
History of diabetes	1 (14.3)	1 (8.3)	1 (12.5)
History of stroke	0	5 (41.7)	1 (12.5)
Smoking	1 (14.3)	4 (33.3)	0
3-day or longer hospital stay	0	1 (8.3)	1 (12.5)
Bed rest	0	0	0

Abbreviations: BMI, body mass index; DVT, deep vein thrombosis; VTE, venous thromboembolic event.

Six (11.5%) respondents perform postoperative screening (e.g., DVT ultrasound) in all patients undergoing surgery, 12 (23.1%) perform postoperative screening in some patients undergoing surgery, 29 (55.8%) do not screen patients postoperatively, and 5 (9.6%) do not manage this aspect of their care ( Fig. 1B ). Among respondents who screen some patients, the following characteristics prompt screening: history of VTE, older age, elevated BMI, history of cancer, history of diabetes, and smoking. The relative frequency of these characteristics is shown in Table 2 .

Overall, 11 (21.2%) respondents perform radiographic screening for VTE in some or all patients preoperatively, and 18 (34.1%) respondents screen at least some or all patients postoperatively ( p  = 0.14).

Regarding perioperative VTE chemoprophylaxis, 36 (69.2%) respondents treat all patients, 8 (15.4%) treat some patients, and 8 (15.4%) do not administer perioperative chemoprophylaxis ( Fig. 1C ). Among respondents who administer chemoprophylaxis in some patients only, the following characteristics prompt treatment: history of VTE, older age, elevated BMI, history of cancer, history of diabetes, female gender, history of stroke, and bed rest. The relative frequency of these characteristics is shown in Table 2 .

Of the respondents who treat CD patients with chemoprophylaxis perioperatively, 26 (59.1%) give low molecular weight heparin, 14 (31.8%) give unfractionated heparin, 1 (2.3%) give direct oral anticoagulants, and 3 (6.8%) give aspirin ( Table 3 ). Twenty-nine (61.5%) start chemoprophylaxis within 24 hours of surgery, 14 (31.8%) start within 48 hours of surgery, and 1 (2.3%) start within 72 hours of surgery ( Table 3 ). Thirty-one (65.9%) only administer chemoprophylaxis while the patient is in the hospital, but 13 (29.5%) continue it postdischarge. Duration of postdischarge ranges from 1 week (2, 4.5%), to 2 weeks (3, 6.8%), to 4 weeks (8, 18.2%) postoperatively ( Table 3 ). These results are not significantly different on chi-square analysis.

Table 3. Medication choice, timing, and duration of pharmacologic thromboprophylaxis.

Characteristic	n (%)
Medication choice
Low molecular weight heparin	26 (59.1)
Unfractionated heparin	14 (31.8)
Aspirin	3 (6.8)
Oral anticoagulants	1 (2.3)
Timing
Within 24 hours of surgery	29 (65.9)
Within 48 hours of surgery	14 (31.8)
Within 72 hours of surgery	1 (2.3)
Duration
During hospital stay	31 (70.5)
1 week postoperatively	2 (4.5)
2 weeks postoperatively	3 (6.8)
1 month postoperatively	8 (18.2)

Twenty-eight (53.8%) respondents perceive the VTE risk in this patient population to be 0 to 5%, 16 (30.8%) perceive the risk to be 6 to 10%, and 8 (15.4%) perceive it to be 11 to 20% ( Fig. 2 ). Utilizing Fisher's exact test, there are no significant differences in preoperative or postoperative screening or in perioperative chemoprophylaxis between surgeons in academic and nonacademic practice settings and between surgeons practicing within and outside of the United States.

Fig. 2.

Perceived risk of perioperative venous thromboembolic event (VTE) in Cushing's disease.

Discussion

This study identifies a high degree of variability in practice patterns surrounding VTE screening and chemoprophylaxis in CD patients undergoing TSS. Most respondents do not perform radiographic screening for VTE. Those that do perform radiographic screening do so postoperatively, rather than preoperatively. Most respondents (84.6%) administer chemoprophylaxis in at least some patients, and chemoprophylaxis duration varies from during the hospital stay only (70.5%) to up to 1 month postoperatively (18.2%). There is also variability in chemoprophylaxis approach and timing. The majority (53.3%) of respondents perceived the risk of perioperative VTE in CD to be 0 to 5%, and no respondents perceived the risk to be > 20%.

Hypercoagulability in CD is multifactorial and related to both an increase in prothrombotic factors (von Willebrand factor, fibrinogen, protein C, protein S, factor VIII, decreased mean activated partial thromboplastin time) and an inhibition of fibrinolytic factors, which do not immediately resolve after hormonal cure. ^{2 4 5 6 7 8} This is compounded by the metabolic comorbidities characteristic of CD (diabetes mellitus, hypertension, obesity). ⁹ CD exacerbates all three elements of Virchow's triad: hypercoagulability, venous stasis via hemodynamic changes, and endothelial dysfunction, which is in turn exacerbated by surgery. ¹ The risk of VTE is higher in CD compared to CS overall, and hypercoagulability persists after hormonal cure. ³

There is limited retrospective evidence for perioperative chemoprophylaxis after TSS in CD patients. Barbot at al report that their incidence of VTE in CD patients was reduced from 2% to 0 after switching their institutional practice from 14 days of fractionated heparin to 30 days of low molecular weight heparin after surgery. ¹⁰ McCormick at al report a 4.5% incidence of VTE complications in patients receiving 5,000 units of subcutaneous heparin daily until hospital discharge compared to a 0% incidence of VTE complications in patients receiving 40 mg enoxaparin nightly until hospital discharge. ¹¹ There is no published evidence on the efficacy of oral anticoagulants or aspirin in this patient population.

According to the 2021 Pituitary Society guidelines, there is no consensus for timing or duration of prophylactic anticoagulation in CD patients. ¹² Prophylaxis is recommended in the perioperative setting for all patients and in patients with additional risk factors (history of VTE, abnormal coagulation testing, preoperative hypercortisolism, current use of estrogen or oral contraception, extended hospital stay, poor mobility, and high postoperative cortisol levels). ¹² In addition, the authors recommend nonpharmacologic measures such as early mobilization and use of compression stockings and/or sequential compression devices. ¹² The Pituitary Society advocates for administering low molecular weight heparin instead of oral anticoagulants due to long half-life and the complexity and cost of oral anticoagulant reversal. ¹²

Given the prevalence of obesity in CD patients, another consideration is the limited availability of data on optimal low molecular weight heparin dosing in people with high BMI. The American College of Chest Physicians guidelines recommend weight-based rather than fixed dosing in this patient population, ¹³ although a 2021 meta-analysis did not find a difference in efficacy and safety based on dosing approach for unfractionated and low molecular weight heparin. ¹⁴ There is also indirect evidence from orthopaedic surgery patients that the use of aspirin may be appropriate for VTE prophylaxis in nonorthopaedic surgery patients. ¹³

The need for chemoprophylaxis should be balanced with the risk of postoperative bleeding after TSS. ¹⁵ A 2010 to 2015 study of the Nationwide Readmissions Database reported a 0.7% risk of epistaxis after TSS for pituitary adenoma, while a 2018 single-institution study reported an epistaxis rate of 1.1%. ^{16 17} This single-institution study also reported a 1.1% risk of postoperative hematoma after TSS for pituitary adenoma. ¹⁷ A feared complication is suprasellar hematoma, which can affect vision. ¹⁸ However, most CD tumors are small without significant suprasellar extension, implying a lower risk of suprasellar hematoma and likely facilitating earlier chemoprophylaxis postoperatively. This is corroborated by a retrospective study, which identified tumor diameter > 30 mm and suprasellar extension as the only independent predictors of sellar hematoma requiring reoperation in patients undergoing TSS for pituitary adenoma. ¹⁹ The risk of postoperative hematoma requiring reoperation was 1.5%. ¹⁹ This is contrasted with risks of VTE in CD patients of 2 and 4.5%. ^{10 11}

Based on the elevated VTE risk after TSS for CD, it appears that chemoprophylaxis postoperatively in addition to mechanical prophylaxis is warranted. ^{3 10 11 20} Based on prior data, it appears that starting subcutaneous heparin within 24 hours postoperatively carries low risk of sellar hematoma or epistaxis. However, the total duration of chemoprophylaxis (e.g., in-hospital only, 7, 14, or 28 days) remains uncertain.

There is a need for rigorous evaluation of the risks and benefits of perioperative chemoprophylaxis in CD patients. A multicenter, randomized controlled trial comparing a chemoprophylaxis strategy (e.g., low molecular weight heparin starting within 24 hours of surgery for 30 days postoperatively) with no chemoprophylaxis is a potential study design strategy to address this question. A randomized controlled trial (NCT04486859) comparing mechanical thromboprophylaxis alone versus mechanical thromboprophylaxis plus low molecular weight heparin (24 hours postoperatively) followed by rivaroxaban (5 days postoperatively) in patients undergoing TSS for CD is underway in China, but has not posted interim results.

Study limitations include selection bias and a risk of duplicate responses given that the survey was distributed twice anonymously. In addition, this survey is unable to differentiate between institutional practice and individual surgeon responses, meaning that certain management approaches may be inflated in frequency if two surgeons from the same institution with one overarching policy both responded to the survey. The majority of respondents were from the United States, so this survey may not fully reflect international practices. The response rate to the survey is low at 3%. However, a large number of the mailing list members in both societies do not perform transsphenoidal surgeries or do not participate in the postoperative management of CD patients and thus would not be able to respond to the survey, so the true denominator to calculate the response rate is likely much lower. The reported incidence of pituitary adenomas in the United States is 4.07 per 100,000, ²¹ and 4% of those patients have CD, ²² suggesting an approximate incidence of approximately 500 CD cases per year in the United States. A prior study using the National Inpatient Sample (NIS) reported that approximately 5,410 TSS are performed in the United States per year by approximately 825 surgeons. ²³ The majority of these surgeons (534) did 5 or less transsphenoidal cases per year, whereas only 131 surgeons had > 20 transsphenoidal operations per year (after correcting for NIS weighting). In addition, of all transsphenoidal pituitary surgeries, only approximately 7% (approximately 380 cases per year) were coded for CD. Based on this, a reasonable estimate on the number of surgeons doing pituitary surgery for CD in the United States is likely somewhere between 200 and 300, yielding an estimated response rate of 17%.

Conclusion

Although hypercoagulability is a known phenomenon, there is still great variability in VTE detection and postoperative prevention practice patterns in CD patients. This study highlights the need for increased awareness about this issue, as well as the need for prospective studies to clarify optimal pharmacologic chemoprophylaxis strategies and duration in this patient population.