key: cord-0878228-2zotqreu
authors: Dong, Fen; Zhen, Kaiyuan; Zhang, Zhu; Si, Chaozeng; Xia, Jiefeng; Zhang, Tieshan; Xia, Lei; Wang, Wei; Jia, Cunbo; Shan, Guangliang; Zhai, Zhenguo; Wang, Chen
title: Effect on Thromboprophylaxis among Hospitalized Patients Using a System-wide Multifaceted Quality Improvement Intervention: Rationale and Design for a Multicenter Cluster Randomized Clinical Trial in China
date: 2020-05-07
journal: Am Heart J
DOI: 10.1016/j.ahj.2020.04.020
sha: e2388effbb8ca0373f331595d9f0ebd1a816b786
doc_id: 878228
cord_uid: 2zotqreu

ABSTRACT Background Venous thromboembolism (VTE) is a life-threatening disease that can affect each hospitalized patient. But the current in-hospital thromboprophylaxis remains suboptimal and there exists a large gap between clinical practice and guideline-recommended care in China. Methods To facilitate implementation of guideline recommendations, we conduct a multicenter, adjudicator-blinded, cluster-randomized clinical trial, aiming to assess the effectiveness of a system-wide multifaceted quality improvement (QI) strategy on VTE prophylaxis improvement and thromboembolism reduction in clinical setting. Hospitals are randomized into intervention or control group. In intervention group, hospitals receive the concept of appropriate in-hospital thromboprophylaxis plus a multifaceted QI which encompasses four components: (1) an electronic alert combining computer-based clinical decision support system and electronic reminders, (2) appropriate prophylaxis based on dynamic VTE and bleeding risk assessments, (3) periodical audit and interactive feedback on performance, (4) strengthened training and patient education. In control, hospitals receive the concept of recommended prophylaxis alone without QI. Thromboprophylaxis will be at the discretion of hospitals and conducted as usual. With a final sample size of 5760 hospitalized patients in 32 hospitals on mainland China, this trial will examine the effect of QI on improvement in thromboprophylaxis and patient-centered outcomes. This is an open-label trial that patients and healthcare professionals will know group allocation after enrollment, but endpoint adjudicators and statisticians will be blinded. RCT# NCT04211181 Conclusions The system-wide multifaceted QI intervention is expected to facilitate implementation of recommended VTE prophylaxis in hospital, thereafter reducing VTE incidence and relevant adverse events among hospitalized patients in China.

Venous thromboembolism (VTE) is an emerging health threat affecting hospitalized patients. Approximately 55-60% VTE are hospital-associated VTE (HA-VTE) that occur during hospitalization or within 90 days after discharge 1 , underlying more than 50% of VTE burden on population 2 . It is a global problem faced across countries 1 To enhance healthcare providers' adherence to recommended care and facilitate implementation of appropriate thromboprophylaxis, we develop a system-wide multifaceted quality improvement (QI) strategy. A multidisciplinary group of hospital staff (doctors, nurses, administrators, pharmacists, etc) from a wide range of departments will be engaged to carry out the QI. Given that each inpatient has at least one VTE risk factor during hospital stay 2, 15 , QI strategy needs to be comprehensive and systematic for the delivery of thromboprophylaxis to all patients. To examine its effectiveness on VTE reduction and determine how best to implement the recommended prophylaxis, we conduct a multicenter cluster randomized trial.

Eligible hospitals will be selected from Chinese Prevention Strategy for Venous J o u r n a l P r e -p r o o f 7 / 40 conduct this multicenter trial to assess effect of QI on thromboprophylaxis in a large-scale patient population. Initially, this trial was scheduled to start in February but delayed due to COVID-19 outbreak. Currently, the epidemic is under control and hospitals are returning to normal work. We will continue to perform this study with a baseline survey to assess hospital eligibility in April and complete hospital randomization in the following month.

The primary objective of this study is to determine whether the system-wide multifaceted intervention increases appropriate VTE prophylaxis rate in hospitalized patients and decreases incidence of any hospital-associated VTE within 90 days after hospital admission. The secondary objective is to reduce safety events, including death incidence (i.e. all-cause mortality, VTE-related mortality) and complications related to prophylactic interventions (e.g. major and clinically relevant non-major bleeding, thrombocytopenia) during the 90-day follow up.

In this multicenter two-armed adjudicator-blinded cluster randomized trial, 32 eligible hospitals are selected from CHIPS-VTE study network, which includes 558 secondary and tertiary hospitals across mainland China. Randomization and interventions are convened at hospital level. During the study period, hospitals in both arms will receive the concept of appropriate VTE prophylaxis. In QI group, a multifaceted J o u r n a l P r e -p r o o f 8 / 40 intervention will be delivered systematically to facilitate implementation of the recommended care while hospitals in control just receive the concept without QI.

In-hospital thromboprophylaxis will be at the discretion of hospitals according to usual care. This is an open-label trial that group allocation will not be blinded to either patients or healthcare professionals. To objectively assess outcomes, adjudicators not involving in study design will assess outcomes. The study is anticipated to be completed in 12 months, starting from hospital selection, patient enrollment, intervention in hospital, 90-day follow up after admission, and data collection of the last patient ( Figure 1 ).

To ensure implementation of quality improvement intervention during study period, participating hospitals will be selected from tertiary hospitals where electronic information systems are accessible and computer-based clinical decision support system (CDSS) can be embedded. The eligible hospitals will be determined within Chips-VTE network ( Figure S1 ). We plan to select 32 hospitals fulfilling eligible criteria and enroll 180 patients consecutively at each hospital (Table 1) . See Statistical Analysis Plan section for details on sample size estimation. The enrollment is expected to be completed within the first 1-2 months.

The study population comprises patients admitted to nine high-risk departments ( enrolled consecutively until the sample size is met. Intervention is applied to all inpatients admitted to the target departments.

We will conduct a baseline survey for hospital eligibility assessment, including hospital characteristics (hospital grade, availability of HIS, medical and surgical departments, etc.), hospital directors' willingness to participate in the study, and current status of in-hospital thromboprophylaxis. There are 558 tertiary and secondary hospitals in CHIPS-VTE network. We deploy a stratified sampling method to select hospitals from the network ( Figure S1 for details).

Stratified permuted block randomization will be adopted to assign hospitals into either QI or usual care group. Hospitals are units for randomization with group allocated at hospital level. By stratifying hospitals into those above or under the median prophylaxis rate obtained in baseline survey, hospitals alphabetically ordered by names will be randomized into each group with a varying block size of 2 or 4 within strata. The randomization procedures will be organized centrally by statisticians in the randomization center. To guarantee blindness to group allocation, hospital J o u r n a l P r e -p r o o f 10 / 40 enrolment phase, an independent recruiter responsible for enrollment will be masked to hospital allocation. They will not know the allocation sequence until eligible patients are enrolled. Afterwards, interventions assigned to the hospital will be delivered to individual patients by doctors.

At each hospital, we schedule to enroll 180 eligible patients consecutively with an average number of 20 hospitalized patients enrolled from 9 departments. Patients admitted to the targeted departments and signing informed consent will undergo assessment for eligibility in screening phase. The enrolled patients and those with screen failure will be compared to evaluate potential selection bias. After enrollment, patients receive interventions assigned to hospitals.

In the newly issued guidelines 12-14 , risk stratification is recommended to guide appropriate thromboprophylaxis. Each patient needs undergo VTE and bleeding risk assessments, particularly when they are admitted, transferred to another department, or their disease conditions change greatly. Validated risk score toolkits are utilized for this dynamic risk monitoring. Identifying patients at diverse risk for VTE and bleeding helps determine appropriate prophylactic interventions. If patients are at risk of VTE and have bleeding risk factors (eg, recent bleed, thrombocytopenia, active bleeding) 16 , mechanical intervention, eg. graduated compression stockings, J o u r n a l P r e -p r o o f 11 / 40 intermittent pneumatic compression, and venous foot pumps, is the appropriate prophylaxis approach. It is an alternative for patients contraindicative to anticoagulant prophylaxis, the use of which could lead to bleeding and safety events. If patients have low bleeding risk, pharmacological prophylaxis is preferred over mechanical ones. Overall, both thrombosis and bleeding risk assessments are recommended for an optimal decision-making in clinic practice. Thromboprophylaxis approaches may need adjustment accordingly due to patients' changing risk during hospital stay ( Figure 2 , Figure 3 ).

To implement the aforementioned recommendations, we design a multifaceted QI intervention, which entails four components that interact mutually. It is applied in a wide variety of inpatient settings, including surgical and medical patients. conditions, transfer to another department and discharge. Data in EMR will be captured to ascertain the implementation of risk assessment and appropriateness of prophylactic prescriptions. In case of uncompleted risk assessment or improper prophylaxis intervention, medical records submitted by medical staff will be blocked and an e-alert will be sent to remind the staff to correct. Performance adjustments are needed until requirements are met. All the computer programs and e-alertness will be well designed and tested in the hospitals assigned to QI group.

Simultaneously, real-time data monitoring and feedback will be accomplished via the electronic system. A cyclical model of predefined performance measures is designed to automatically analyze and provide feedback on quality of prophylaxis.

When administering QI intervention, doctors and nurses' behaviors will be reviewed and audited by health administrators. Some in-process metrics (VTE and bleeding risk assessments within 24 hours after admission, dynamic risk assessment, appropriate VTE prophylaxis) and outcome metrics (HA-VTE incidence, clinically relevant bleeding and mortality) will be calculated and sent to medical staff and health J o u r n a l P r e -p r o o f 13 / 40 administrators via CDSS for audit.

(2) Dynamic VTE/bleeding risk assessments Risk factors for hospital-associated VTE are well characterized, enabling the use of VTE risk assessment to identify high-risk population for early and appropriate prophylaxis. According to existing evidence 17,18 , we recommend the use of Caprini risk score for VTE risk assessment in surgical patients while Padua risk score be used to assess VTE risk in medical patients ( Table 2 ). All admitted patients undergo VTE assessment. Nurses perform the initial assessment and doctors confirm the results.

Meantime, patients' age, comorbidities, trauma history, medications, invasive procedures and other factors are assessed for bleeding risk by doctors. As disease conditions change during hospital stay, patients need to be assessed for VTE and bleeding risk repeatedly. Dynamic assessments are scheduled to be done at admission, transfer to another department, a significant change in disease conditions, and at discharge.

(3) Regular audit and interactive feedback on performance Performances of medical staff (doctors and nurses) are audited monthly by VTE prevention committee, which comprises hospital directors, medical and nursing directors, and health administrators. Using the audited data, the committee sends reports to medical staff, including the overall thromboprophylaxis, in-process and outcome metrics, root-cause analysis of VTE safety events, and measures for quality improvement. In the context of missed risk assessments or inappropriate prophylaxis J o u r n a l P r e -p r o o f 14 / 40 delivered, an electronic alert will remind health administrators, who in return send feedback to responsible medical staff and urge them to administer interventions in accordance with the recommended care. The initial feedback will be followed by an electronic reminder. Medical staff's performances may need to be adjusted until the expected prophylaxis is delivered properly.

(4) Strengthened hospital staff training and patient education on VTE Hospital directors and health administrators will receive trainings on the concept of HA-VTE prevention, overall goal and operation mechanisms, and challenges that need to be tackled with. The trainings will be provided within 30 days after hospital randomization. Medical education focusing on VTE risk assessment, prevention, diagnosis and treatment will be convened to doctors, nurses, pharmacists and other medical staff per quarter. The knowledge of VTE are based on newly published guidelines and consensus 6-9,12-14 . Likewise, education sessions will be offered to patients and family caregivers to increase their awareness on VTE general knowledge.

Doctors or nurses provide the education when patients are admitted and discharged.

During hospitalization, nurses will also instruct patients on the use of graduated compression stockings (GCS) or intermittent pneumatic compression (IPC). If not using correctly, patients will receive strengthened education until using these devices correctly. At discharge, guidance on thromboprophylaxis or anticoagulant regimen will be provided for patients or those remaining at high risk of VTE.

J o u r n a l P r e -p r o o f 15 / 40 In hospitals allocated to control group, patients will undergo usual care at the discretion of hospitals. VTE risk assessment and prophylactic interventions will be performed according to existing practice in hospitals. Nearly 70% surgeons responding to the survey routinely prescribed LMWH for patients with lung resection during hospitalization. Acetylsalicylic acid was still used as a prophylaxis approach in common practice. Time for starting VTE prophylaxis was usually 1 day after operation. The two surveys display current prophylaxis for HA-VTE in China. To better understand usual care in control group in this study, we will conduct a baseline survey in recruited hospitals before cluster randomization, collecting information on VTE and bleeding risk assessment, prophylactic approaches, initiating time for prophylaxis, etc.

As our study population are medical or surgical patients admitted to the nine J o u r n a l P r e -p r o o f 16 / 40 departments with high VTE incidence, patients in both arms will receive treatments targeted to diseases responsible for the admission. The treatment patterns and disease management will be at the discretion of doctors. Additionally, VTE incidence and bleeding events within 90 days are important outcomes for effect and safety assessment. To enhance patients' self-reported outcomes, education on signs and symptoms of VTE and bleeding will be delivered to patients during hospitalization in both groups.

Due to the nature of interventions, both doctors administering interventions and patients will know group allocation after enrollment. To ensure equal attention to two arms, data collectors, endpoint adjudicators, and statisticians will be blinded to group allocations. Before intervention, a randomization schedule for hospitals will be pre-generated by an independent statistician unaware of hospital identity. During the intervention period, data managers and statisticians remain blinded to group assignment in data collection and monitoring. An independent data monitoring board will evaluate the trial data and safety. In order to objectively evaluate outcomes, adjudicators assessing thromboprophylaxis implemented in hospitalized patients, imaging results for VTE diagnosis and other endpoints will be blinded.

The primary endpoint is appropriate prophylaxis rate in hospitalized patients, defined bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact with a physician, temporary cessation of study treatment, or discomfort of pain or impairment of activities of daily life 21 . HIT is a fall in platelet count of >50% from the highest platelet count after the start of heparin use with a positive laboratory test 22 . Safety events will be collected by phone visits at day 60 and 90 after admission. Any endpoint or adverse events occurring during study period will be recorded.

During study period, some key in-process and outcome metrics will be regularly monitored (Table S1 ). Caprini or Padua scores, begun with the initial assessment within 24 hours at admission until the last one at discharge, will be recorded in medical records. Bleeding assessments are recorded simultaneously. Appropriate prophylaxis is determined by VTE and bleeding risk. Mechanical or pharmaceutical interventions are adopted accordingly. To enhance medical staff's awareness on appropriate prophylaxis, trainings on indications and contraindications to mechanical prophylaxis or therapeutic anticoagulation treatment will be delivered per quarter. For to mechanical or therapeutic treatment are embedded into CDSS system to prompt doctors while prescribing prophylactic regimen. In this study, data collection starts from patient enrollment and continues until completion of the last patient follow up.

Figures S2 demonstrates the process of data management and quality control.

Sample size is estimated based on the primary analysis of group difference in VTE prophylaxis rate among hospitalized patients. The nationwide survey on thromboprophylaxis in China demonstrates an appropriate prophylaxis rate of 10.3% in hospitalized patients 4 . Assuming a target clinical difference of 5% absolute increase through QI intervention, we anticipate an appropriate prophylaxis rate of 15.3% in QI group. In this cluster trial with hospitals as unit of randomization, between-cluster variation is indicated by intra-cluster correlation coefficient (ICC), one typically used index for such variation 23 . ICC is determined as 0.01 according to prior studies 24, 25 .

Given the same cluster size with an equal number of patients per hospital (cluster), we plan to enroll 180 patients from each hospital and approximately 20 patients from each of the nine target departments. To compare between-group prophylaxis rates with 1:1 allocation, 90% power, 5% significance level, a cluster size of 180, 0.01 ICC and 10% attrition, the sample size is calculated as 5722 patients according to J o u r n a l P r e -p r o o f 21 / 40 accessible to study investigators or authorized personnel. To comply with data safety regulations, only staff at the study center have access to patients' information.

This study is approved by ethics committee in China-Japan Friendship Hospital (approval number 2016-SSW-7) and will be approved by ethnic committee in each hospital. It has been registered at www.clinicaltrials.gov (NCT04211181).

In this multicenter cluster randomization trial, intervention is applied at hospital level. Written consent will be obtained from directors at hospital level with agreement for participation and randomization, avoiding selection bias potentially induced by differences in consent refusal between hospitals [27] [28] [29] . QI intervention is supposed to be beneficial in HA-VTE prevention among hospitalized patients through effective implementation of recommended prophylaxis. Each participating hospital prefers to receive the QI interventions. To reduce hospital withdrawal, the QI interventions, if proven effective, will be delivered to all hospitals randomized to control group after completion of this study.

In patient enrollment process, informed consent will be obtained from patients as well. Written consent includes consent for information routinely collected in hospital, willingness to provide complementary data specific to this study, and permission for 90-day follow up. Due to chronology of individual patient recruitment after hospital randomization in clustered randomization trial 28 , this study is prone to selection bias J o u r n a l P r e -p r o o f 22 / 40 induced by unblinded recruiters or patients who are informed or aware of hospital allocation. To prevent such bias, recruiters in each hospital will be blinded to group allocation and enroll patients independently. Partial information rather than full information will be provided to patients in enrollment process to avoid opt-out option in patients. The hospital allocation will not be specified to patients until they are enrolled and undergo intervention. Chinese hospitalized patients and their unmet need in thromboprophylaxis 4 . The QI can also be introduced into routine clinical practice to enhance care quality and reduce VTE-related safety events. A systematic approach for HA-VTE prevention in NHS England has been demonstrated to be effective in reducing post-discharge deaths with a 15.4% reduction in 90-day mortality 1 , indicating importance of a system-wide and multifaceted intervention for effective prevention of HA-VTE and its related deaths.

Given the great disparities in health care systems, hospital protocols and structures across nations and cultures, CHIPS-VTE study will provide data on systematic and multifaceted implementation's effect on patient outcomes in developing countries.

The present study has the following unique features: (1) a multi-center cluster randomized trial is designed to minimize contamination across groups; (2) uses of CDSS and e-alertness in a wide variety of inpatient settings increase their applicability in daily practice. Application of CDSSs in this study will meet the increasing demand for health information technology regarding the growing concerns about quality of medical care in hospital; (3) real-time and mutually interactive quality control via CDSS enable QI intervention implemented properly among multidisciplinary hospital staff; (4) a pilot study has been done to test the feasibility of multifaceted QI in clinical setting, enhancing feasibility of this multi-center trial; (5) behavioral intervention in healthcare professionals through QI and usual practice in control will provide real-world evidence on effectiveness of QI on thromboprophylaxis improvement. The pragmatic design increases generalizability of Meanwhile, there are several inherent limitations in this study. First, this is a cluster randomization trial with hospitals being randomized as clusters. Hospital randomization occurs before patient enrollment, making allocation concealment difficult. Selection bias may arise when unblinded recruiters don't enroll patients because their hospitals are not allocated to the group they expect to be in, which may also lead to hospital withdrawal 30 . In addition, consent bias could be induced by patients who have been informed of or get known the group allocation before enrollment 28, 30 . To minimize these bias inherent in methodology, informed consent needs to be handled differently from traditional randomized trials, in which randomization and intervention are administered at individual level. We will obtain well-informed written consent from hospital directors and agree to provide QI intervention to hospitals in control group after completion of the study. In patient enrollment phase, information on group allocation will not be provided to patients until they are enrolled. A blinded recruiter unaware of hospital allocation will recruit patients independently. With respect to effectiveness evaluation in this study, QI To select representative hospitals, we deploy a stratified sampling method based on geographic regions (northeast, north, east, south central, northwest, and southwest China) and

baseline VTE prophylaxis quality (median prophylaxis rate by region obtained from the survey). In each region, the number of selected hospitals will be proportional to the number of candidate hospitals. Noteworthily, some core hospitals that provide optimal care in the region will be chosen purposively to represent the high quality of care in China. Taking non-response into consideration, we increase the sampling rate to approximately 10%. If directors in selected hospitals decline to participate, the remaining unselected hospitals will be sampled randomly until a total of 32 eligible hospitals are recruited.

During the study period, information on patients' demographic characteristics, care provided, risk assessments, interventions and others will be entered into CDSS. Illogical data entries, (1) Tertiary hospitals with >500 beds that provide VTE diagnosis and care, deliver medical education, and conduct research.

(2) Have departments in which admitted patients are at increased risk for VTE and thrombotic events can easily occur in routine procedures. The departments that typically have high VTE incidence are Respirology, ICU, Neurology, Orthopaedics, General Surgery, Vascular Surgery, Neurosurgery, Oncology, and Gynecology.

(3) Hospital electronic information system is accessible and CDSS can be embedded for real-time monitoring and mandatory implementing QI intervention during the study;

(4) Directors of hospitals wish to improve in-hospital VTE prophylaxis and are willing to conduct multifaceted QI intervention systematically.

(1) Hospitals that have already conducted QI intervention systematically 

Preventing hospital associated venous thromboembolism

Interventions for implementation of thromboprophylaxis in hospitalized patients at risk for venous thromboembolism

The Cochrane database of systematic reviews

Trends in the incidence of pulmonary embolism and deep venous thrombosis in hospitalized patients

VTE Risk Profiles and Prophylaxis in Medical and Surgical Inpatients: The Identification of Chinese Hospitalized Patients' Risk Profile for Venous Thromboembolism (DissolVE-2)-A Cross-sectional Study

Trends in Hospitalization and In-Hospital Mortality From VTE

Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report

Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis

Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis

Prevention and management of hospital-associated venous thromboembolism

Prevention, treatment and management of hospital-asociated venous thromboembolism

Guidelines on the diagnosis, management and prevention of pulmonary thromboembolism

Heparin-Induced Thrombocytopenia

Measures of between-cluster variability in cluster randomized trials with binary outcomes

Primary care management for optimized antithrombotic treatment [PICANT]: study protocol for a cluster-randomized controlled trial

Developments in cluster randomized trials and Statistics in Medicine. Statistics in medicine

Methods for sample size determination in cluster randomized trials

Effect of a Quality Improvement Intervention With Daily Round Checklists, Goal Setting, and Clinician Prompting on Mortality of Critically Ill Patients: A Randomized Clinical Trial

Participant informed consent in Rationale and Design for a Multicenter Cluster Randomized Clinical Trial in China Fen Dong

Admin 6 ; Tieshan Zhang, MD 6 ; Lei Xia

PhD 2,3,4,11 ; on behalf of Chinese Prevention Strategy for Venous Thromboembolism

Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 6 Department of information management

Formal analysis, Writing -Original Draft, Visualization. Kaiyuan Zhen: Investigation, Writing -Original Draft, Visualization. Zhu Zhang: Investigation, Writing -Review & Editing. Chaozeng Si: Software, Jiefeng Xia: Software, Resources. Tieshan Zhang: Software, Resources. Lei Xia: Investigation, Resources. Wei Wang: Investigation, Resources. Cunbo Jia: Resources. Guangliang Shan: Methodology. Zhenguo Zhai: Conceptualization, Methodology

Effect on Thromboprophylaxis among Hospitalized Patients Using a System-wide Multifaceted Quality Improvement Intervention: Rationale and Design for a Multicenter Cluster Randomized Clinical Trial in China Fen Dong

Admin 6 ; Tieshan Zhang, MD 6 ; Lei Xia

PhD 2,3,4,11 ; on behalf of Chinese Prevention Strategy for Venous Thromboembolism

Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 6 Department of information management

We thank all hospital directors within CHIPS-VTE network to participate in baseline survey and hospital eligibility assessment. Doctors, nurses, health administrators, researchers, and patients' engagement in the study will be appreciated.

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

 Unmet clinical need in thromboprophylaxis remains in Chinese hospitalized patients  The first pragmatic trial for improving in-hospital thromboprophylaxis in China  Multifaceted quality improvement facilitates implementation of thromboprophylaxis  Hospitals are randomized to either quality improvement intervention or routine care  Real-world effectiveness of intervention on thromboprophylaxis is assessed