Postoperative Initiation of Thromboprophylaxis in Patients with Cushing’s Disease (PIT-CD):

Posted on June 28, 2025 by MaryO

Abstract

Background

Pituitary surgical intervention remains the preferred treatment for Cushing’s disease (CD) while postoperative venous thromboembolism (VTE) is a significant risk. Whether to prescribe pharmacological thromboprophylaxis presents a clinical dilemma, balancing the benefit of reducing VTE risk with the potential for increasing hemorrhagic events in these patients. Currently, strong evidence and established protocols for routine pharmacological thromboprophylaxis in this population are lacking. Therefore, a randomized, controlled trial is warranted to determine the efficacy and safety of combined pharmacological and mechanical thromboprophylaxis in reducing postoperative VTE risk in patients with CD.

Methods

This investigator-initiated, multi-center, prospective, randomized, open-label trial with blinded outcome assessment aims to evaluate the efficacy and safety of combined pharmacological and mechanical thromboprophylaxis compared to mechanical thromboprophylaxis alone in postoperative patients with CD. A total of 206 patients diagnosed with CD who will be undergoing transsphenoidal surgery will be randomized in a 1:1 ratio to receive either combined pharmacological and mechanical thromboprophylaxis (intervention) or mechanical thromboprophylaxis only (control). The primary outcome is the risk of VTE within 12 weeks following surgery.

Discussion

This trial represents a significant milestone in evaluating the efficacy of combined pharmacological and mechanical prophylaxis in reducing VTE events in postoperative CD patients.

Trial registration

ClinicalTrials.gov Identifier: NCT04486859, first registered on 22 July 2020.

Peer Review reports

Administrative information

Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).

Title {1} Postoperative Initiation of Thromboprophylaxis in patients with Cushing’s Disease (PIT-CD): a randomized control trial
Trial registration {2a and 2b} ClinicalTrials.gov Identifier: NCT04486859, first registered on 22 July 2020

WHO Trial Registration Data Set (Supplement)
Protocol version {3} Date: 1 July 2021, Version 5.0
Funding {4} The trial is supported by Clinical Research Plan of SHDC (SHDC2020CR2004A).
Author details {5a} Nidan Qiao, Min He, Zhao Ye, Wei Gong, Zengyi Ma, Yifei Yu, Zhenyu Wu, Lin Lu, Huijuan Zhu, Yong Yao, Zhihong Liao, Haijun Wang, Huiwen Tan, Bowen Cai, Yerong Yu, Ting Lei, Yan Yang, Changzhen Jiang, Xiaofang Yan, Yanying Guo, Yuan Chen, Hongying Ye, Yongfei Wang, Nicholas A. Tritos, Zhaoyun Zhang, Yao Zhao.
Name and contact information for the trial sponsor {5b} Investigator initiated trial, principal investigators, post-production correspondence:

Yao Zhao (YZ), Department of Neurosurgery, Huashan Hospital, Fudan University, 12 mid Wulumuqi Rd, Shanghai 200040, China. Email: zhaoyao@huashan.org.cn

Zhaoyun Zhang (ZZ), Department of Endocrinology, Huashan Hospital, Fudan University, 12 mid Wulumuqi Rd, Shanghai 200040, China. Email: zhangzhaoyun@fudan.edu.cn
Role of sponsor {5c} The trial sponsor holds responsibility for all key elements of the trial’s execution, including its design, data collection, management, analysis, interpretation of results, and reporting. An independent Data Safety Monitoring Board monitors data safety and participant protection to ensure the trial’s integrity and the safety of participants.

Introduction

Background and rationale {6a}

Cushing’s disease (CD) is characterized by hypercortisolism resulting from an adrenocorticotropic hormone-secreting pituitary adenoma [1]. Tumor-directed surgical intervention remains the preferred treatment for this condition. Patients with Cushing’s disease commonly experience a hypercoagulable state due to activation of the coagulation system [2], suppression of anticoagulation and fibrinolytic pathways, and enhanced platelet activation, significantly increasing their risk of venous thromboembolism (VTE). Postoperative VTE risk is further exacerbated by factors such as intravenous medications, blood loss, and prolonged bed rest. Multiple studies report postoperative VTE risks in patients with CD ranging from 3 to 20% [2,3,4,5].

The Endocrine Society and Pituitary Society recommends considering perioperative thromboprophylaxis as a strategy to reduce VTE risk in patients with CD [1, 6]. However, this recommendation was based on a single study that investigated perioperative prophylactic anticoagulation in patients with Cushing’s syndrome [7]. The study was limited by its small sample size, single-center nature, and retrospective design. Crucial details such as the optimal timing for initiation, choice of anticoagulant, and duration of therapy were not established. Recent surveys of European and US centers indicate that thromboprophylaxis protocols are not routinely employed, and there is considerable heterogeneity in prophylactic practices across centers [8, 9].

The primary risk associated with thromboprophylaxis is postoperative hemorrhage. In patients with CD, although the risk of bleeding is significantly lower than after a typical craniotomy, complications such as intrasellar hemorrhage and nasal bleeding may still occur. Due to its retrospective nature, the aforementioned study cannot conclusively determine whether the benefits of thromboprophylaxis outweigh its risks. Consequently, guidelines from hematology and neurosurgical societies have concluded that the current evidence is insufficient to support a standardized VTE prophylaxis regimen for neurosurgical patients [10,11,12]. Nevertheless, both the American Society of Hematology and European guidelines suggest that a combination of pharmacological and mechanical prophylaxis may be justified for higher-risk subgroups [10, 13].

Objectives {7}

Due to conflicting recommendations and lack of a definitive study to determine whether the benefits outweigh the risks regarding the use of pharmacological antithrombotic prophylaxis in patients with CD following pituitary surgery, we initiated this study, called Postoperative Initiation of Thromboprophylaxis in Patients with Cushing’s Disease (PIT-CD). The aim of this study is to evaluate whether the combined use of pharmacological and mechanical prophylaxis reduces VTE events compared to mechanical prophylaxis alone in postoperative CD patients.

Trial design {8}

Our hypothesis was that pharmacological prophylaxis in combination with intermittent pneumatic compression would be superior to intermittent pneumatic compression alone.

The PIT-CD study is an open-label, multicenter, prospective, randomized clinical trial with open-label treatment designed to assess the efficacy of combined pharmacological and mechanical prophylaxis compared to mechanical prophylaxis alone. Patients are randomized in a 1:1 ratio. The patient flow is illustrated in Fig. 1.

Fig. 1
figure 1

Patient flow

Methods: participants, interventions and outcomes

Study setting {9}

This study was initiated in tertiary centers across China with expertise in managing patients with CD. Currently, seven centers (see Supplements) are actively recruiting patients for the study.

Eligibility criteria {10}

Inclusion criteria

Patients are eligible for inclusion if they meet the following criteria:

  1. 1.Age between 18 and 65 years (inclusive)
  2. 2.Diagnosed with CD and scheduled to undergo transsphenoidal surgery
  3. 3.Either newly diagnosed or recurrent disease

A diagnosis of CD is confirmed based on the following criteria:

  1. A.Twenty-four-hour urine free cortisol > upper normal boundary and low-dose dexamethasone suppression test (overnight or over two days): serum cortisol > 1.8 µg/dL
  2. B.8 AM serum adrenocorticotropic hormone > 20 pg/mL
  3. C.High-dose dexamethasone suppression test: serum cortisol or 24-h urine cortisol suppression > 50%
  4. D.Inferior petrosal sinus sampling (IPSS) indicates elevated adrenocorticotropic hormone central gradient consistent with secretion from a central source

Patients are diagnosed with CD if both criteria A and B are met, in addition to either C or D. In patients with tumors smaller than 6 mm on MRI, IPSS indicating a central source is essential.

Exclusion criteria

Patients will be excluded from the study if they meet any of the following criteria:

  1. 1.History of VTE before surgery or within 24 h post-surgery
  2. 2.Acute bacterial endocarditis
  3. 3.Major bleeding events within the previous 6 months
  4. 4.Thrombocytopenia
  5. 5.Active gastrointestinal ulcers
  6. 6.History of stroke
  7. 7.High risk of bleeding due to clotting abnormalities
  8. 8.Participation in other clinical trials within the last three months
  9. 9.Contraindications to rivaroxaban (e.g., renal dysfunction with eGFR < 50 mL/min)
  10. 10.Presence of malignant diseases
  11. 11.Severe mental or neurological disorders
  12. 12.Presence of intracranial vascular abnormalities
  13. 13.Contraindications to mechanical prophylactic anticoagulation
  14. 14.Pregnancy
  15. 15.Any other condition that researchers deem inappropriate for study participation (e.g., oral contraceptive use, history of thrombophilia)

Who will obtain informed consent? {26a}

Patients with CD are provided with detailed information about the clinical trial, including known and foreseeable risks and potential adverse events. Investigators are required to thoroughly explain these details to the patients or their guardians if the patients lack capacity to provide consent. Following a comprehensive explanation and discussion, both the patients or their guardians and the investigators sign and date the informed consent form.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

N/A. Biological specimens are unnecessary in this trial. Participant data was not intended to be included in any other ancillary studies.

Interventions

Explanation for the choice of comparators {6b}

Participants in the control arm of the study will be required to use a limb compression system twice daily, for 30 min each session, from the 2nd to the 7th day post-surgery. The intermittent pneumatic compression devices are the standard of care in the prevention deep vein thrombosis in many literatures [14, 15].

Intervention description {11a}

Participants in the intervention arm of the study will be required to use the same limb compression system, also for 30 min twice daily from the 2nd to the 7th day post-surgery. Additionally, participants will receive subcutaneous injections of low molecular weight heparin (4000 IU) once daily from the 2nd to the 4th day post-surgery. Starting on the 5th day and continuing through the 28th day post-surgery, participants will take oral rivaroxaban tablets (10 mg) once daily.

Criteria for discontinuing or modifying allocated interventions {11b}

Participants have the right to withdraw their consent at any time without providing a reason, thereby terminating their participation in the study. Any withdrawal and the reasons, if known, will be documented. Criteria for premature termination include the following: occurrence of the primary outcome (patients will still be monitored for safety for 12 weeks), failure to meet inclusion criteria, fulfillment of exclusion criteria, or loss of contact.

Strategies to improve adherence to interventions {11c}

Several strategies will be employed to maintain adherence to interventions in this trial. Participants will receive thorough preoperative education on the importance of pharmacological and mechanical prophylaxis in preventing VTE if they are assigned to the intervention arm or the importance of mechanical prophylaxis if they are assigned to the control arm. Detailed instructions on the use of the limb compression system and administration of rivaroxaban will be provided. Pill counts will be performed to document adherence in the intervention group.

Relevant concomitant care permitted or prohibited during the trial {11d}

N/A. Participants in both groups will receive treatment according to the current standard-of-care.

Provisions for post-trial care {30}

Participants experiencing adverse events will be followed until the events are resolved. Other participants will be regularly followed in accordance with clinical routine clinical practice. Participants in the trial are compensated in the event of trial-associated harms.

Outcomes {12}

Primary outcome

The primary outcome of the study is the risk of venous thromboembolism (VTE) within 12 weeks after surgery. VTE is defined as either deep vein thrombosis (DVT) or pulmonary embolism (PE), regardless of whether the cases are symptomatic or asymptomatic.

Secondary outcomes

The secondary outcomes are as follows: (1) risk of DVT within 12 weeks after surgery; (2) risk of PE within 12 weeks after surgery; (3) risk of symptomatic DVT, symptomatic PE, or symptomatic VTE within 12 weeks after surgery; (4) risk of VTE-associated mortality within 12 weeks after surgery; (5) risk of all-cause mortality within 12 weeks after surgery.

“Symptomatic” is defined as the presence of one or more of the following symptoms attributed to VTE: pain or swelling in the affected leg; chest pain, dyspnea, or decreased oxygen saturation.

Safety outcomes

Safety outcomes include the following: (1) major bleeding; (2) minor bleeding; (3) hemorrhage-associated surgery; (4) hemorrhage-associated readmission; (5) coagulation disorders (APTT or INR > 2.5 normal upper boundary); (6) thrombocytopenia; (7) increase in liver function tests.

Major bleeding is defined according to the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis [16]. This includes fatal bleeding; bleeding that is symptomatic and occurs in a critical area or organ; extrasurgical site bleeding causing a fall in hemoglobin level of 20 g/L or more, or leading to transfusion of two or more units of whole blood or red cells; surgical site bleeding that requires a second intervention.

Participant timeline {13}

A schema of all trial procedures and clinical visits is summarized in Table 1.

Table 1 Schedule of enrolment, interventions and assessments

Sample size {14}

Our estimates are based on a retrospective study examining the effects of preventive anticoagulation during the perioperative period in Cushing syndrome [7]. This study reported that the risk of postoperative VTE was lower in patients receiving preventive anticoagulants (6%) compared to those who did not (20%). Therefore, we assume that the risk of the primary outcome in the control group is 20%, while in the intervention group it is 5% within 12 weeks. Based on these assumptions, we calculated the required sample size for each group to be is 93 using PASS software, with an alpha level of 0.05 and a power of 0.9. Accounting for an estimated 10% dropout rate, the total number of patients required is 206.

Recruitment {15}

Clinical investigators will receive training on communicating with potential patients and their relatives, documenting screening logs, and other standard operating procedures during the kick-off meeting at each participating center. All centers will recruit patients competitively, and recruitment progress will be monitored to track the process. The estimated recruitment rate is 8 to 10 patients per month, with an expected recruitment period of 2 years.

Assignment of interventions: allocation

Sequence generation {16a}

The randomization procedure is computer- and web-based, and is stratified by age (≤ 35 years old vs. > 35 years old), sex (female vs. male) and disease duration (≤ 2 years vs. > 2 years).

Concealment mechanism {16b}

Participants are randomized using a web-based randomization system (edc.fudan.edu.cn). This system maintains allocation concealment by withholding the randomization code until screening is complete.

Implementation {16c}

Investigators will enroll participants, with the stratified block algorithms generating a random allocation sequence. Participant assignment through the randomization system is not subject to influence by the clinical investigators.

Assignment of interventions: blinding

Who will be blinded {17a}

This is an open-label trial, meaning that both the treating physicians and the participants are aware of the treatment allocation. However, a separate group of clinical outcome assessors (Clinical Event Committee, CEC), who are blinded to the treatment allocation, will determine the clinical outcomes. Similarly, lower limbs ultrasound and pulmonary computed tomography angiography (CTA) assessments will be adjudicated by an Independent Review Committee (IRC) that is blinded to the treatment allocation. Statisticians remain blinded to treatment allocation prior to the final analysis, and the interim analyses will be conducted by a separate team from the one undertaking the final analysis.

Procedure for unblinding if needed {17b}

N/A. The design is open label.

Data collection and management

Plans for assessment and collection of outcomes {18a}

Deep vein thrombosis (DVT) will be assessed using bilateral lower limb ultrasound. Asymptomatic participants will undergo evaluation at prespecified intervals (day 4, day 7, week 4, and week 12 post-intervention), while symptomatic individuals will receive immediate imaging upon presentation of clinical manifestations such as unilateral or bilateral lower extremity edema or pain. Pulmonary embolism (PE) screening will be performed via pulmonary computed tomography angiography (CTA) at day 7 in asymptomatic cases, with expedited assessment triggered by acute symptoms (e.g., chest pain, dyspnea) or radiographic evidence of DVT detected during lower limb ultrasonography. These events will be adjudicated by an Independent Review Committee (IRC). A CEC will be convened to assess other outcomes.

Plans to promote participant retention and complete follow-up {18b}

The initial intervention for participants takes place during the patient’s inpatient stay, during which researchers will provide detailed information about the required procedures. Participants will undergo routine follow-up at 4 weeks and 12 weeks post-surgery, with VTE-related follow-up arranged during these routine visits. Transportation and examination expenses for follow-up visits are reimbursable.

Data of those who discontinue will also be documented.

Data management {19}

Data will be kept, both on paper and in electronic databases, for at least 5 years. Data will be entered by clinical investigators using electronic case report forms (eCRFs) on a web-based platform (http://crip-ec.shdc.org.cn). The investigators will be introduced to the platform and trained in data entry during the initial kick-off meeting before the recruitment of the first study participant. Access to the study database will be restricted to authorized clinical investigators, who will use a personal ID and password to gain entry.

Confidentiality {27}

When adding a new participant to the database, identifying data (e.g., Chinese name) are entered on a form that is printed but not saved on the server. On this form, participants will be represented by a unique ID. The printed form is kept in a locked space accessible only to the principal investigator and may be used to unblind personal data if necessary.

Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

N/A. There will be no biological specimens collected.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

The primary analysis will be conducted on the full analysis data set, adhering to the intention-to-treat principle, which includes all patients randomized in the study. Generalized linear models (GLMs) with binomial distribution will be employed to analyze primary, secondary, and safety outcomes. Treatment effects for these outcomes will be quantified as risk differences (RDs) with corresponding 95% confidence intervals (CIs). Additionally, odds ratios with 95% confidence intervals will be calculated using a logistic regression model, and hazard ratios with 95% confidence intervals will be calculated using a Cox Proportional model.

Safety analyses will be based on all randomized patients who have received the study treatment. The risk and percentages of adverse events (AEs) and serious adverse events (SAEs) will be summarized by treatment group. Instances of subject death will be summarized and listed. All analyses will be performed using the SAS system, version 9.4.

Interim analyses {21b}

The Data Safety Monitoring Board (DSMB) plans to convene the interim analysis meeting after randomization and 12-week follow-up visits are completed for 103 participants. The significance level for interim analysis (primary outcome) is set at 0.001 according to the Haybittle–Peto boundary principle.

Based on these analyses, the DSMB will advise the steering committee on whether the randomized comparisons in this study have demonstrated a clear benefit of the intervention. If the p-values from the interim analysis for both groups are less than 0.001, recruitment will be halted, and the study will meet the criteria for early termination. If the p-values are greater than or equal to 0.001, recruitment will continue until the planned sample size is achieved, with the final analysis significance level set at 0.049.

Methods for additional analyses (e.g., subgroup analyses) {20b}

For both primary and secondary outcomes, pre-specified subgroup analyses will be conducted based on sex, age, disease duration, and magnitude of urine free cortisol elevation.​

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

The primary analysis will be conducted on the intention-to-treat data set, which includes all randomized patients and is based on the treatment arm to which they were assigned, regardless of the therapy they actually received. A per-protocol analysis will also be performed to account for non-adherence. If appropriate, multiple imputation will be used to address any missing data in the dataset. The prespecified statistical analysis plan (SAP), developed by independent biostatisticians blinded to treatment allocation, will be prospectively registered on ClinicalTrials.gov prior to database lock.

Plans to give access to the full protocol, participant-level data and statistical code {31c}

The trial was prospectively registered in ClinicalTrials.gov with the Identifier NCT04486859. Updates to reflect significant protocol amendments will be submitted. The statistical analysis protocol will also be updated prior to database locking. The datasets and statistical code are available from the corresponding author upon reasonable request.

Oversight and monitoring

Composition of the coordinating centre and trial steering committee {5d}

The trial steering committee is composed of four Chinese experts and two international experts from outside of China. Investigators in participating centers are required to attend a training course during a kick-off event organized by the principal investigator. Each investigator must confirm that they have been properly introduced to trial-specific procedures. An IRC will adjudicate primary outcomes. An independent CEC will be responsible for ensuring high-quality outcomes and minimizing inconsistencies or bias in the clinical trial data.

Composition of the data monitoring committee, its role and reporting structure {21a}

The Data Safety Monitoring Board (DSMB) consists of three members, including one statistician. The DSMB will regularly receive blinded statistical reports and monitor serious adverse events throughout the trial to assess patient safety and determine if the trial should be terminated prematurely due to safety concerns.

An initial DSMB meeting will be conducted to ensure that DSMB members fully understand the research protocol, review and approve the DSMB charter, assess the monitoring plans for safety and efficacy data, and discuss the statistical methods, including stopping rules. A second DSMB meeting will be conducted to review the interim analysis. The interim analyses and the treatment allocation data will be provided by an independent trial statistician and provided confidentially to the DSMB chairman. An ad hoc DSMB meeting may be convened by either the principal investigators or the DSMB if imminent safety issues arise during the trial.

Adverse event reporting and harms {22}

Adverse events (AEs) and serious adverse events (SAEs) are defined according to the ICH GCP guidelines. All AEs and SAEs reported by study participants or observed by investigators within the study period must be documented in the eCRF and reported to the DSMB. Additionally, SAEs must be reported to the IRB.

Anticipated adverse events, including both major and minor bleeding events (e.g., epistaxis necessitating readmission), as well as coagulation disorders, thrombocytopenia, and elevated liver function tests, will be prospectively monitored in all trial participants. Unanticipated adverse events (not pre-specified in Section {12}) will be captured through spontaneous reporting. All adverse event data will be classified and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 to ensure consistency. For reporting, we will disclose all protocol-specified adverse events from Section {12}, alongside any unanticipated events higher than Grade 3.

Frequency and plans for auditing the trial conduct {23}

The trial conduct will be regularly audited to ensure compliance with the study protocol and Good Clinical Practice guidelines. Audits will be conducted by independent monitors from Shanghai Shenkang Hospital Developing Centers. These audits will involve reviewing study documentation, informed consent forms, source data verification, and adherence to the protocol. Audits will also assess data entry accuracy and the overall management of the trial. The frequency of these audits will be determined based on the recruitment rate, safety concerns, and previous audit findings.

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

Any modifications to the study protocol will require protocol amendments, which will be promptly submitted for approval to the Institutional Review Board. These changes will only be implemented after receiving approval from the Institutional Review Board. Once approved, ClinicalTrials.gov will be updated to reflect any significant changes. If necessary, protocol training to implement the amendments will be provided by the study team to participating centers.

Dissemination plans {31a}

After database closure and data analysis, the trial statistician will prepare a report detailing the main study results. Following this, a meeting of the investigators will be convened to discuss the findings before drafting a scientific manuscript for peer review and publication in a major scientific journal. Additionally, efforts will be made to present the results at key international conferences of neuroendocrine societies.

Discussion

This trial represents a significant milestone in evaluating the efficacy of combined pharmacological and mechanical prophylaxis in reducing VTE events in postoperative CD patients. To date, no similar randomized controlled trials have addressed this specific clinical question.

Transnasal transsphenoidal pituitary tumor resection is the preferred surgical approach for patients with CD. Compared to craniotomy, transsphenoidal surgery has a significantly lower risk of bleeding. The published literature indicates a bleeding risk of 0.02% following transsphenoidal surgery [17], whereas the incidence of intracranial hemorrhage after craniotomy ranges from 1% to 1.5% [18]. Therefore, for clinical practicality and safety, this study will exclusively include patients undergoing transsphenoidal resection.

Early meta-analyses indicated that low molecular weight heparin is generally safer, with a relatively lower bleeding risk compared to rivaroxaban, particularly when used for thrombosis prevention after hip and knee replacement surgeries [19]. However, recent studies have shown that rivaroxaban may have no significant difference in major bleeding and non-major bleeding risks compared to enoxaparin in thromboprophylaxis following non-major orthopedic surgeries of the lower limbs [20]. Given the risk of postoperative bleeding and the potential bleeding side effects of oral medications, LMWH was chosen for initial postoperative treatment because of its relatively lower bleeding risk. As patients prepare for discharge, the more convenient oral medication was selected for ongoing prophylaxis.

Patients who develop early VTE on the first day after surgery or despite anticoagulant use will be included in a further post hoc analysis. This will help identify risk factors for VTE. This analysis will aim to determine why VTE occurred despite anticoagulant use and explore whether specific factors, such as hypertension, diabetes, body mass index, or disease duration, are associated with increased risk. Based on our findings, recommendations may include earlier initiation of prophylaxis, dosage adjustments, or extended duration of treatment for high-risk patients.

Trial status

This protocol is based on trial protocol version 5.0, dated July 1, 2021. The first patient was enrolled in December 2020, and the final patient is expected to be enrolled by the end of 2024. While the original plan anticipated completing recruitment by December 2022, the COVID-19 pandemic significantly impacted many districts and cities in China, leading to lockdowns that have severely delayed the implementation and recruitment for this trial.

Data availability {29}

Data will be made available from the corresponding author upon reasonable request.

Abbreviations

CD:
Cushing’s disease
VTE:
Venous thromboembolism
DVT:
Deep vein thrombosis
PE:
Pulmonary embolism
CEC:
Clinical events committee
IRC:
Independent Review Committee
CTA:
Computed tomography angiography
eCRFs:
Electronic case report forms
AE:
Adverse events
SAE:
Severe adverse events
DSMB:
Data Safety Monitoring Board

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From https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-025-08923-6

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Venous Thromboembolism in Cushing Syndrome

Posted on May 22, 2024 by MaryO

Abstract

Background

Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE).

Objective

The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis.

Design and methods

A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG’s) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022.

Results

Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3–30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years.

Conclusion

Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed.

Significance statement

The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.

Keywords: endogenous hypercortisolism; Cushing disease; Cushing syndrome; thromboprophylaxis; venous thromboembolism

Introduction

Endogenous hypercortisolism (Cushing syndrome, CS) is a rare disorder with an estimated incidence of 0.2–5.0 cases per million inhabitants per year in various populations, whereas its prevalence is close to 39–79 cases per million (1, 2). The majority of cases are adrenocorticotropic hormone (ACTH) dependent, of which a pituitary corticotrope adenoma (Cushing disease, CD) is the most prevalent cause, whereas ACTH-secreting non-pituitary tumors (ectopic ACTH and corticotropin-releasing hormone syndrome secretion) are responsible for about 5–10% of cases. ACTH-independent cases of CS (adrenal adenomas or uni- or bilateral adrenal hyperplasia) account for the remaining 20% of cases (1, 3).

It is well-known that endogenous hypercortisolism is associated with increased morbidity and mortality (4, 5, 6). This increased risk is mainly driven by cardiovascular events, including venous thromboembolic events (VTEs) such as pulmonary embolism (PE) and deep vein thrombosis (DVT). It has been demonstrated that the primary risk factors associated with VTE include older age (>69 years), reduced mobility, acute severe infections, previous cardiovascular events, higher midnight plasma cortisol levels, and shorter activated partial thromboplastin time (7). Additionally, a recent analysis of the ERCUSYN database found a higher prevalence of VTE among male patients, patients with a history of multiple surgeries, and those with high urinary cortisol levels (8). Several studies have observed an increased risk of VTE in patients with endogenous hypercortisolism even long after successful treatment. A study showed that the VTE incidence is almost seven times higher in the years before diagnosing endogenous hypercortisolism and almost 17 times higher in the first year after diagnosis; this incidence remains increased in the initial months following successful treatment (9). This results in an increased incidence rate of 14.6 per 1000 person-years for VTE in patients with endogenous hypercortisolism compared to the general population (10). The cortisol-induced hypercoagulability is thought to be partially caused by activation of the coagulation cascade with an increase in, e.g. von Willebrand factor, fibrinogen, and factor VIII concentrations (11, 12), impaired fibrinolysis (4) and endothelial dysfunction (13). Changes in pro- and anticoagulant factors may persist after successful surgery or medical therapy for at least several months (14, 15).

Given the lack of evidence from clinical trials, there is a large practice variation regarding thromboprophylaxis management and perioperative medical treatment in patients with endogenous hypercortisolism, even among reference centers that have obtained specific national and international accreditation for the diagnosis and treatment of CS (16). To further map local practice patterns and associated VTE complications in CS, we performed a study across the European Reference Network on Rare Endocrine Conditions (Endo-ERN) expert centers using the European Registries for Rare Endocrine Conditions (EuRRECa), and the contributors to the relevant main thematic groups (MTGs), i.e. Adrenal (one) and Pituitary (six) of the Endo-ERN.

Methods

The main objective of this study was to collect epidemiological and routine clinical data on new CS cases reported on the EuRRECa electronic reporting tool (e-REC) and Endo-ERN with a focus on VTE and thromboprophylaxis.

EuRRECa was constructed to support the needs of Endo-ERN, maximizing the opportunity for all patients, healthcare professionals, and researchers to participate and use high-quality, patient-centered registries for these rare conditions. The two platforms of the EuRRECa project encompass the Core registry, which collects a common dataset and clinician- and patient-reported outcomes, and an electronic surveillance system, the e-Reporting on Rare Endocrine Conditions (e-REC) program (17).

e-REC is a program that monthly captures the number of new cases of rare endocrine conditions seen at the participating centers.

e-REC is used for continuous monitoring of the expert centers of ERNs (Endo-ERN, ERN BOND), for mapping expert centers not only within European Union, for understanding the occurrence of the rare endocrine and bone conditions, and for conducting secondary surveys.

Because e-REC only provides a number of cases with a specific diagnosis without any personal data, there is no informed consent needed. e-REC is open to Endo-ERN and other centers involved in the care of patients with rare endocrine conditions.

Secondary survey

Secondary surveys (https://eurreb.eu/registries/e-rec/secondary-survey/) on e-REC-reported cases allow for the collection of well-defined routine clinical data for quality assurance and for understanding the clinical presentation of the reported condition. No personally identifiable data, such as date of birth, date of surgery, date of VTE, or exact laboratory tests, were collected.

First, the e-REC team sorted e-REC IDs of patients with endogenous hypercortisolism (ORPHA443287, ORPHA1501, ORPHA99408, ORPHA96253) reported between January 2021 and July 2022. Then the centers were provided with the list of IDs and queried to revisit these cases and to add clinical data to the online questionnaire. The survey questionnaire utilized Webropol survey, a secure online tool endorsed and supported by NHS Greater Glasgow & Clyde and NHS Scotland. The use of e-REC and secondary surveys was approved by the institutional board of the Leiden University Medical Center, and participating centers were advised to seek local approval if needed.

In addition, healthcare providers (not reporting in e-REC) of the relevant main thematic groups (‘Adrenal’ and ‘Pituitary’) of Endo-ERN were queried regarding any of their reported new encounters with a confirmed diagnosis of CS from January 2021 to July 2022. Patients with suspected but not confirmed CS were excluded (according to the current guideline) (18).

VTE in CS survey

The survey was open for entry from October 2022 to June 2023. Follow-up started on the date of initial CS diagnosis (within the period of interest – January 2021 till July 2022) and ended when an endpoint of interest occurred (VTE, bleeding, death) or on the date of filling in the questionnaire, whichever came first.

A survey was designed consisting of questions on the occurrence of VTE, and if so, additional questions assessed risk factors of VTE, treatment regimens, and VTE complications. Questions included data about relevant co-morbidities and the different items of the Cushing severity index (CSI) – a validated score for reliable clinometric evaluation of severity in endogenous hypercortisolism (19) using eight different parameters (fat distribution, skin lesions, muscle weakness, mood disorders, hypertension, diabetes mellitus, hypokalemia, and sex-related disturbances), each one graded from 0 to 2 with a maximum score of 16. These components enabled the calculation of the CSI score of all subjects. For the full questionnaire, see Annex 1 (see section on supplementary materials given at the end of this article).

Statistical analyses

Continuous data are presented as mean ± s.d. (range) and were compared using ANOVA. All the other values, if not normally distributed, are expressed as median with interquartile range (IQR) and compared using ANCOVA. Statistical analysis was performed using SPSS version 25.0.

The individual person-time was calculated based on the dates of reporting in e-Rec and filling in the survey and on the date of VTE. Incidence rates for VTE were calculated by dividing the observed number of VTE cases within the study period by the sum of individual person-years and were presented with accompanying 95% CI. Any VTE occurring before diagnosis was ignored in the estimation of the incidence rate.

Results

Patient characteristics

The survey was completed by 35 clinicians in 20 centers from six countries (Fig. 1). Within the 18-month study period, a total of 222 new patients were reported with endogenous hypercortisolism. The mean follow-up period was 15 ± 8 months (range 3–30). The total number of person-years was 274. Table 1 shows the clinical and demographic characteristics of patients with CS.

Figure 1View Full Size
Figure 1

Overview of countries responding to the survey.

Citation: Endocrine Connections 13, 6; 10.1530/EC-24-0046

Table 1Clinical and demographic characteristics of patients with Cushing syndrome of different origin.

Demographic/clinical variable Cushing disease Adrenal Cushing syndrome Ectopic Cushing syndrome Total
Number of patients: n (%) 141 (63.5%) 69 (31.1%) 12 (5.4%) 222 (100%)
Age (years): median (IQR) (range) 43 (22.5) (7–79) 46 (25.5) (3–80) 48 (37) (22–77) 43 (25) (3–80)
Female: n (%) 105 (74.4%) 54 (78.2%) 6 (50%) 165 (74.3%)
СSI: mean ± s.d. 5.77 ± 2.88 4.81 ± 2.72 8.5 ± 2.87 5.6 ± 2.9
Number of comorbidities: mean ± s.d. 1.9 ± 1.58 1.97 ± 1.39 2.17 ± 1.7 1.93 ± 1.53
Obesity: n (%) 49 (34.8%) 23 (33.3%) 4 (33.3%) 76 (34.2%)
Hypertension: n (%) 90 (63.8%) 49 (71%) 9 (75%) 148 (66.7%)
Diabetes: n (%) 30 (21.3%) 17 (24.6%) 5 (41.7%) 52 (23.4%)
Previous VTE: n (%) 9 (6.4%) 2 (2.9%) 0 11 (4.9%)
VTE: n (%) 4 (2.8%) 1 (1.4%) 1 (8.3%) 6 (2.7%)
Cortisol-lowering treatment: n (%) 60 (42.6%) 14 (20.2%) 10 (83.3%) 84 (37.8%)
Thromboprophylaxis: n (%) 103 (73%) 41 (59.4%) 10 (83.3%) 154 (69.3%)
Surgery: n (%) 133 (94.3%) 64 (92.8%) 7 (58.3%) 204 (91.9%)

CSI, Cushing severity index; VTE, venous thromboembolism.

 

One hundred forty-one patients had Cushing’s disease (64%), 69 had ACTH-independent CS (31%), and 12 patients had ectopic CS (5.4%). One hundred sixty-five (74%) were female with a mean age of 44 ± 16 years (range 3–80). Ninety-one patients (41%) were overweight (BMI 25–30 kg/m2), and 76 (34%) were obese (BMI ≥ 30 kg/m2). A previous VTE (not related to CS based on the clinical judgment of the reporters, information on the time of occurrence was unavailable) was reported in 11 (4.9%) patients, and other cardiovascular events (e.g. myocardial infarction, myocarditis, cerebrovascular disease, and stroke) in 11 patients (4.9%). Most patients underwent surgery (n = 204, 92%), pituitary (n = 130, 64%), adrenal surgery (n = 68, 33%), and other surgery (n = 6, 3%); 47 (23%) of them had repeated surgery.

The mean number of comorbidities was 2 ± 1.5 (range 0–10). In 36 (16.2%) patients, no relevant comorbidities were reported, and 25 had more than 4 (11%). Mean CSI was 5.6 ± 2.9 (0–13), patients with CD had higher scores compared to patients with adrenal CS 5.8 ± 2.9 vs 4.8 ± 2.7 (MD 1.0; 95% CI 0.2; 1.8). Patients with ectopic CS had the highest scores (8.5 ± 2.9), with a mean difference of 3.7 (95% CI 2.0; 5.4) compared to adrenal CS, and a mean difference of 2.7 (95% CI 1.0; 4.4) when compared to CD.

Cortisol-lowering medical treatment

Eighty-four patients (38%) received pre-surgical cortisol-lowering medical treatment, the majority receiving metyrapone (68%) or ketoconazole (30%). Other used agents were osilodrostat (8%), mitotane (1%), and levoketoconazole (1%). Of the pre-treated patients, 60 had CD (43% of the total CD group), 14 had adrenal CS (20% of the total adrenal CS group), and 10 had ectopic CS (83% of the total ectopic CS group). Patients with CD and ectopic CS were treated more often in comparison with patients with adrenal CS, with OR 2.9 (1.5; 5.7), P = 0.0019 and OR 19.6 (3.9; 100), P = 0.0003, respectively.

There were no major differences in patient characteristics between pre-treated and non-pre-treated patients in terms of age (44 ± 17 vs 43 ± 15 years; MD 1.0; 95% CI −3.4; 5.4), sex distribution (65/83 vs 101/138, OR 1.3; 95% CI 0.7; 2.5), number of comorbidities (1.8 ± 1.2 vs 2.0 ± 1.8; MD 0.2; 95% CI −0.2; 0.6), and CSI (6.2 ± 3.0 vs 5.4 ± 2.8; MD 0.8; 95% CI 0.01; 1.6).

Medical cortisol-lowering treatment was initiated at the time of diagnosis in 59 cases (70%) and usually discontinued 1 day before or after surgery (91%). Hypercortisolism was completely controlled in 43 patients (21%) and partially controlled in 40 (20%) before surgery, irrespective of disease origin (based on the cortisol levels).

VTE prophylaxis

Protocolled and unprotocolled initiation of thromboprophylaxis

A thromboprophylaxis protocol specific for patients with CS was present in 6 out of 20 centers (30%), while three centers (15%) had no thromboprophylaxis protocol, and 11 out of 20 (55%) had a protocol not specific for CS. Thromboprophylaxis was given to 154 out of 222 patients (69%); in 15 cases (9.7%), this was a therapeutic treatment due to a previous event/condition. Thromboprophylaxis was initiated from CS diagnosis onward in 43 cases (28%): thirty-one patients (31/43, 72%) were from centers (n = 3) with specific thromboprophylaxis protocols for patients with CS, and consequently, the treatment was initiated at the time of diagnosis. The remaining 12 patients (28%) started thromboprophylaxis due to the presence of risk factors such as severe CS, older age, limited mobility, active malignancy, or additional cardiovascular comorbidities. Thromboprophylaxis was initiated 2−6 weeks before surgery – in nine cases (5.8%), 1 week before surgery – in eight cases (5.2%), the day before/of surgery in 50 cases (33%), and after surgery – in 26 cases (19%). The remaining 30% of patients did not receive any thromboprophylaxis. In three cases (1.9%), data about the initiation of thromboprophylaxis were missing. In patients with CD, therapy was started more often on the day before/of surgery (40%) compared to adrenal CS patients (20%), OR 2.7 (95% CI 1.1; 6.5). At the same time, thromboprophylaxis was more often prescribed after surgery in patients with adrenal CS (12/41 vs 13/103; OR 2.86 (95% CI 1.1; 7.0)). The use of elastic compressive stockings was reported in 83 (37%) of patients.

Thromboprophylactic agents and duration of treatment

Low-molecular-weight heparins (LMWHs) were prescribed in the vast majority of cases, with n = 147 (96%). Nadroparine was used in 57 patients (39%), with a dose ranging from 2850 to 5700 IU per day depending on BMI. Enoxaparin, ranging from 4000 to 6000 IU per day, was prescribed in 52 patients (35%), while dalteparin, ranging from 2500 to 5000 IU per day, was used in 32 patients (22%). Other drugs included tinzaparin and fondaparinux. Direct oral anticoagulants (DOACs) were used in only six patients (3.9%) (with dosages ranging from 10 to 20 mg/day for rivaroxaban and 2.5–10 mg/day for apixaban), and warfarin was prescribed in one patient (0.6%).

Thromboprophylaxis was discontinued during the first week after surgery in 55 patients (36%), during 2–4 weeks in 28 patients (18%), 6–12 weeks in 26 patients (17%), and was continued longer in 17 patients (11%). The median pre- and postoperative duration of thromboprophylaxis was 14 days (IQR = Q3–Q1 = 28–7 = 21).

Differences between patients that received and those that did not receive thromboprophylaxis

The 68 patients not receiving any thromboprophylaxis had lower CSI scores 4.3 ± 2.5 vs 6.2 ± 2.9 (MD 1.9; 95% CI 1.1; 2.8), and more often did not undergo surgery, 12/68 vs 6/154 (OR 5.3 (95% CI 1.9; 14.8)). Within the cohort of patients with CD, thromboprophylaxis was prescribed more often to older patients (45 ± 15 vs 37 ± 15 years) and to patients with higher CSI (6.1 ± 2.8 vs 4.7 ± 2.7, MD 1.4, 95% CI 0.4; 2.4). Among the patients with adrenal CS, thromboprophylaxis was initiated more often with higher CSI (5.8 ± 2.9 vs 3.6 ± 1.9, MD 2.2, 95% CI 0.9; 3.5), but no differences were observed in age and number of comorbidities (MD 4.6, 95% CI (−4.0; 13.2) and MD 0.1 (−0.5; 0.8), respectively).

Bleeding complications

No major bleeding was reported; two patients reported epistaxis, not related to pituitary surgery.

Venous thromboembolic event

Six cases of VTE were reported (2.7%, 95% CI 1; 6), (Table 2): four patients with CD, one patient with adrenal CS, and one patient with ectopic CS. At the time of VTE, 5 out of 6 had uncontrolled hypercortisolemia.

Table 2Clinical and demographic characteristics of patients with Cushing syndrome of different origin and VTE.

Demographic/clinical variable Case 1 Case 2 Case 3 Case 4 Case 5 Case 6
Type of CS CD CD CD CD Benign adrenal CS Ectopic CS
Sex F F F M M F
Age 48 55 33 54 35 39
Risk factors Overweight

Hypertension

Osteoporosis with fractures

 Obesity

Hypertension

Previous VTE

 Obesity

Hypertension

Repeated pituitary surgery

 Obesity

Hypertension

Previous VTE

Diabetes

 Overweight

Hypertension

Osteoporosis with fractures

Previous VTE

 Hypertension
CSI 7 5 7 5 1 11
Medical treatment No No Yes (controlled CS) No No Yes (uncontrolled CS)
TPX start 1 week pre-op The day of surgery 1 week pre-op Before Dz of CS Before Dz of CS From diagnosis
TPX stop 2 weeks post-op 1 week post-op 6 weeks post-op Ongoing DOAC Ongoing LMWH Ongoing LMWH
TPX type Nadroparine Nadroparine Nadroparine Rivaroxaban Fondaparinux Tinzaparin
VTE type Central retinal vein occlusion PE Thrombophlebitis with thrombus v. cephalica PE + DVT PE Inferior vena cava thrombosis resulting to death
VTE timing 12 weeks pre-op 6 weeks post-op 9 days post-op 24 months before diagnosis 4 weeks before diagnosis Was not operated

CSI, Cushing severity index; CS, Cushing syndrome; CD, Cushing disease; DVT, deep vein thrombosis; DOAC, direct oral anticoagulants; LMWH, low-molecular-weight heparin; PE, pulmonary embolism; TPX, thromboprophylaxis; VTE, venous thromboembolism.

 

Three patients (3/6) had a previous VTE, and most of them had several additional risk factors for thrombosis. There were three cases of PE (one combined with DVT), one case of central retinal vein thrombosis, and one case of thrombophlebitis with thrombus of the vena cephalica. The patient with ectopic CS died because of thrombosis of the vena cava inferior despite cortisol-lowering treatment with four different agents and thromboprophylaxis with LWMH treatment. VTE episodes were registered during a very wide time frame: from 2 years before the diagnosis of CS to 6 weeks after surgery. One VTE episode was reported in the group of patients with elastic stockings usage (1/83), three in group without stockings (3/121), and two in the group with unknown status (OR 0.7 (95% CI 0.1; 8.1)).

The incidence rate of VTE after CS diagnosis in this survey was 14.6 (95% CI 5.5; 38.6) per 1000 person-years (four events for 274 person-years).

The incidence rate of VTE in CS of different origins in patients receiving thromboprophylaxis was 10.2 (95% CI 2.6; 40.5) vs 25.6 (95% CI 6.5; 100.7) cases per 1000 person-years without thromboprophylaxis (two events for 196 person-years vs two events for 78 person-years), which was an incidence rate ratio between the two groups of 2.5 (95% CI 0.18; 34.7), P > 0.05.

Discussion

The results of this study, which represent real-world clinical data of patients treated for CS in European reference centers, are consistent with previous cohort studies and demonstrate similar rates. In the presence of heterogeneous policies on thromboprophylaxis in expert centers throughout Europe, our study also provides better insight into the various policies on pre-surgery cortisol-lowering treatment. We found that the incidence rate of VTE in patients with CS was 14.6 (95% CI 5.5; 38.6) per 1000 person-years, and VTE occurred even in patients on cortisol-lowering medication and anticoagulants.

A specific thromboprophylaxis protocol for patients with CS was not available in the vast majority of centers, despite the fact that retrospective cohort studies have shown a decrease in VTE-associated mortality and morbidity in patients with endogenous hypercortisolism on anticoagulant treatment (20, 21). Thromboprophylaxis in CS patients has been reported to be associated with low bleeding rates (22, 23), which is confirmed in the present study.

The optimal timing for initiation of thromboprophylaxis probably depends on the risk profile of individual patients (especially patient’s mobility) and remains unclear, which is reflected by the diverse start dates in our study: 28% of patients started at the time of CS diagnosis, 33% the day before/of surgery, and 19% directly after surgery. The duration of thromboprophylaxis is also unclear and differed greatly among the study population. At present, different studies have confirmed that the risk of VTE remains increased at least until 3 months after successful surgery and may normalize after 6 months (9, 24). Prolonging thromboprophylaxis with LMWH until 30 days after surgery appears to reduce the VTE incidence in patients with CD without any significant side effects (9, 14, 20). Of note, in our study, half of the VTE events (n = 3) occurred despite active thromboprophylaxis, highlighting the fact that thromboprophylaxis (or dosages which were used) may be insufficient in the highest risk categories, such as previous VTE and ectopic CS. Unfortunately, the design of the secondary survey does not allow us to answer the question of whether the doses were adapted accordingly to glomerular filtration rate and weight. Nowadays, it is generally accepted that hypercortisolism per se is an important risk factor for VTE, although a relation between the severity of hypercortisolism and changes in coagulation factors has not been demonstrated (11). Consequently, it seems beneficial to start cortisol-lowering treatment in patients with CS while awaiting curative surgery regardless of thromboprophylaxis, to decrease the risk of postoperative withdrawal syndrome. This might be beneficial for the postoperative VTE risk as the corticosteroid withdrawal syndrome is a pro-inflammatory, and thus a pro-thrombotic, state in itself, thereby theoretically reducing the risk of VTE (11). Unfortunately, no clinical guidance exists on this topic, which is reflected by the real-world outcome data of this study. Initiation of cortisol-lowering medication varies from center to center and between countries and also depends on the origin of the underlying disease. As observed in this study, only 20% of patients with adrenal CS were treated with cortisol-lowering medication vs 83% of patients with ectopic CS and 43% of patients with Cushing’s disease. It is plausible to assume that this reflects both differences in disease severity and differences in the pre- and peri-operative management of adrenal and neurosurgical surgeries and the availability or lack of surgical procedures. In agreement with this, it has been suggested that in patients pretreated with cortisol-lowering medication before surgery, VTE risk was lower than patients not receiving cortisol-lowering medication before surgery (10). However, a recent larger study of the European Registry on Cushing syndrome (ERCUSYN) did not observe differences in post-surgical morbidities including thromboembolism within 180 days of surgery (6), although the proportion of patients receiving thromboprophylaxis in their study was lower, which may have influenced the results. Similar data were published in a more recent analysis of the ERCUSYN database (8). However, it has been reported that patients with higher cortisol levels (blood samples measured at midnight and free cortisol measured in urine) also had a higher VTE risk (7, 8, 25). The present study did not detect a difference in VTE risk between the different types of endogenous hypercortisolism, as in other studies, probably due to the small number of events. Also, other preventive measures, such as early mobilization after surgery and the use of elastic compressive stocking until mobilization, may have a role in the management of thromboprophylaxis, but we have not found difference within the groups in our survey (20).

Our study has some limitations as it was a retrospective survey, which may have introduced selection and detection bias. The secondary survey design limits the access to exact data (as precise date of VTE, surgery, details on previous VTE, adjustment of LMWH dosage for weight and others), so the dataset is rather different from a single-center chart review. Even with the use of e-REC, we cannot be sure that all new cases of CS have been included in the registry and in the survey. Also, several centers have reported less than five cases. Additionally, the date of e-REC registration is probably not the exact date of diagnosis, since there could be referral delay before patients are seen in a tertiary center. This might affect the VTE incidence rate.

Moreover, the total number of patients and events related to VTE is comparatively smaller than in previous studies. This limited dataset poses challenges in drawing robust conclusions regarding predisposing factors, subgroupings, optimal dosages, and clinical strategies for preventing VTEs. All these factors should be taken into account when designing a prospective observational study on the incidence of VTEs in patients with Cushing syndrome. However, we do feel that considering the similarities of our data with previously reported studies, the findings of the survey are consistent with current daily clinical practice throughout different expert centers in Europe. Additionally, the unique setup of this real-world multiple tertiary expert center collaborative study can be a starting point for the prospective registry on the EuRRECa platform aimed at improving best practice.

Conclusion

The incidence rate of VTE in patients after CS diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years.

Of patients with CS, 30% did not receive preoperative thromboprophylaxis, and at the same time, half of the VTE cases occurred despite active thromboprophylaxis. Prospective clinical trials are needed to develop evidence-based guidelines on thromboprophylaxis and harmonized local protocols throughout the Endo-ERN.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/EC-24-0046.

Declaration of interest

NMA-D the LUMC funding (EuRRECa is funded through ENDO ERN within the European Union within the framework of the EU4H Programme, grant agreement no. 101084921). FAK has received research funding from Bayer, BMS, BSCI, AstraZeneca, MSD, Leo Pharma, Actelion, Farm-X, The Netherlands Organisation for Health Research and Development, the Dutch Thrombosis Foundation, the Dutch Heart Foundation and the Horizon Europe Program, all outside this work and paid to his institution. FG has received funding from research purposes from Pfizer, Ipsen, and Camurus. EN is supported by the Clinician Scientist Program RISE (Rare Important Syndromes in Endocrinology), supported by the Else-Kröner-Fresenius Stiftung and Eva Luise und Horst Köhler Stiftung. RP has received research funding from Recordati AG., Corcept Therapeutics, Strongbridge Biopharma, Neurocrine Biosciences; and served as a consultant for Corcept Therapeutics, Recordati AG., Crinetics Pharmaceuticals, H. Lundbeck A/S. SFA (EuRRECa is funded through ENDO ERN within the European Union within the framework of the EU4H Programme, grant agreement no. 101084921). AMP (Endo-ERN is funded by the European Union within the framework of the EU4H Programme, grant agreement no. 101084921). Other co-authors – none. SFA is Editor-in-Chief of Endocrine Connections. SFA was not involved in the review or editorial process for this paper, on which he is listed as an author.

Funding

This publication is supported by Endo-ERN. Endo-ERN is funded by the European Union within the framework of the EU4H Programme, grant agreement no. 101084921.

Acknowledgements

L Bakker (Department of Medicine, Division of Endocrinology, Leiden University Medical Centre, Leiden, Netherlands); S Bensing, K Berinder, M Petersson (Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden); and C Brachet, P Chausseur, B Corvilain, N Driessens, R Fishler (Department of Endocrinology, Hôpital Universitaire de Bruxelles, Hôpital Erasme, Brussels, Belgium).

References

From https://ec.bioscientifica.com/view/journals/ec/13/6/EC-24-0046.xml

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