- Email: [email protected]
VTE Risk Profiles and Prophylaxis in Medical and Surgical Inpatients
[
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Original Research
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Venous Thromboembolism Risk Profiles and Prophylaxis in Medical and Surgical Inpatients
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The Identification of Chinese Hospitalized Patients’ Risk Profile for Venous Thromboembolism (DissolVE-2)—A Cross-sectional Study
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Zhen-guo Zhai, MD, PhD; Quan-cheng Kan, MD; Wei-min Li, MD, PhD; Xin-yu Qin, MD; Jie-ming Qu, MD, PhD;
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Yuan-kai Shi, MD, PhD; Rui-hua Xu, MD, PhD; Yu-ming Xu, MD; Zhu Zhang, MD; Chen Wang, MD, PhD; on behalf of the DissolVE-2 investigators
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Limited data exist on VTE risk and prophylaxis in Chinese inpatients. The Identification of Chinese Hospitalized Patients’ Risk Profile for Venous Thromboembolism-2 (DissolVE-2), a nationwide, multicenter, cross-sectional study, was therefore designed to investigate prevalence of VTE risks and evaluate VTE prophylaxis implementation compliant with the latest prophylaxis guidelines (American College of Chest Physicians [CHEST], 9th edition).
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METHODS:
BACKGROUND:
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Adults admitted ($ 72 h) to 60 urban, tertiary Chinese hospitals due to acute medical conditions or surgery from March to September 2016 were assessed for VTE risk. Risk assessments were made by using the Padua Prediction Scoring or Caprini Risk Assessment model, risk factors, and prophylaxis based on the CHEST guidelines, 9th edition.
29 30 31 32 34 35 36 37 38 39 40 42 43 44 45 47
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A large proportion of hospitalized patients reported VTE risk and low rate of CHEST-recommended prophylaxis. The data highlight the insufficient management of VTE risk and show the great potential for improving physicians’ awareness and current practices across China.
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TRIAL REGISTRY:
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KEY WORDS:
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CONCLUSIONS:
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A total of 13,609 patients (6,986 surgical and 6,623 medical) were analyzed. VTE risk in surgical inpatients was categorized as low (13.9%; 95% CI, 13.1-14.7), moderate (32.7%; 95% CI, 31.6-33.8), and high (53.4%; 95% CI, 52.2-54.6); risk in medical patients was categorized as low (63.4%; 95% CI, 62.2-64.6) and high (36.6%; 95% CI, 35.4-37.8). Major risk factors in surgical and medical patients were major open surgery (52.6%) and acute infection (42.2%), respectively. Overall rate of any prophylaxis and appropriate prophylactic method was 14.3% (19.0% vs 9.3%) and 10.3% (11.8% vs 6.0%) in surgical and medical patients. RESULTS:
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ChiCTR-OOC-16010187.
CHEST 2018;
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89 90 91 92 93 94 95 97 98 99 100 101 102
China; prophylaxis; risk profile; VTE
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50 ABBREVIATIONS:
51 52 53 54 55
Q2
CCU = coronary care unit; CHEST = American College of Chest Physicians AFFILIATIONS: From the Department of Pulmonary and Critical Care Medicine (Drs Zhai, Zhang, and Wang), Center of Respiratory Medicine, China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, No. 2 Yinghua Dongjie, Hepingli, Beijing, China; Department of Pharmacy (Dr Kan), The First Affiliated
Hospital of Zhengzhou University, Henan, China; Department of Pulmonary and Critical Care Medicine (Dr Li), West China Hospital, Sichuan University, Sichuan, China; Department of General Surgery (Dr Qin), Zhongshan Hospital, Fudan University, Shanghai, China; Department of Respiratory Medicine (Dr Qu), Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Department of Respiratory Medicine (Dr Qu), Huadong Hospital
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VTE affects approximately 5% to 15% of patients hospitalized for medical or surgical symptoms.1 The incidence of DVT and pulmonary embolism in the Chinese population (Hong Kong) is estimated to have increased from 17.1 and 3.9, respectively, per 100,000 in 2000 to 20012 to 30.0 and 8.7 per 100,000 in 2010 to 2011.3 This approximate doubling in incidence is probably due to multiple factors, including lifestyle changes, longer life span, heightened VTE awareness, and advances in imaging availability and expertise.3,4
112 113 114 115 116 117 118 119 120 121 122 123
Although early VTE prophylaxis is recommended,5-10 it is reportedly clinically underutilized.11 The multicenter Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting (ENDORSE) study reported that 51.8% of hospitalized patients were at risk of VTE, with only one half of those receiving prophylaxis complying with the American College of Chest Physicians (CHEST) guidelines, 7th edition. Although ENDORSE excluded China and Japan, other Asian ENDORSE substudies reported a VTE risk similar to that of the global population (50.4%). However, CHESTadherent VTE prophylaxis was lower than the overall average (32.1%).12-14
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In 2016, there were, on average, 6,321,000 medical and surgical inpatients in China on a daily basis15 at risk for hospital-acquired VTE. Concern with their
VTE-related risk and management should take into account their thrombosis and bleeding risk profiles and frequency of VTE prophylaxis administration, none of which, to the best of our knowledge, has been studied in detail. The VTE Risk Assessment and Thromboprophylaxis Among Hospitalized Acute Medical Patients in China (RAMP) study16 included ICU and coronary care unit (CCU) patients and showed that the proportion of at-risk patients in China was 57.3%. In addition, only 20.2% of these patients received CHEST-recommended VTE prophylaxis (CCU patients, 22.7%; ICU patients, 16.9%; P ¼ .0117). However, this study omitted nonICU inpatients and reported on 1,247 patients, approximately 0.02% of China’s current daily inpatient census. To understand VTE’s real-world scenario in China, a nationally representative study was required. We therefore designed and conducted the Identification of Chinese Hospitalized Patients’ Risk Profile for Venous Thromboembolism-2 (DissolVE-2) study to identify VTE and bleeding risk factors, estimate the proportions of at-risk hospitalized patients, and report the proportions receiving CHEST-compliant VTE prophylaxis in a large sample of medical and surgical inpatients. DissolVE-2 further evaluated VTE risk by using a combination of risk factor evaluation and prevalent contemporary risk-assessment modeling to facilitate comparisons with survey results from elsewhere.
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affiliated to Fudan University, Shanghai, China; Department of Medical Oncology (Dr Shi), National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Department of Medical Oncology (Dr R. H. Xu), Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong, China; Department of Neurology (Dr Y. M. Xu), The First Affiliated Hospital of Zhengzhou University, Henan, China; Peking Union Medical College (Drs Wang and Zhang), Chinese Academy of Medical Sciences, Beijing, China; and Department of Respiratory Medicine (Dr Wang), Capital Medical University, Beijing, China. A poster reporting this work was presented at the 2018 American Thoracic Society Conference, May 18-23, 2018, San Diego, CA. Drs Zhai and Zhang contributed equally. FUNDING/SUPPORT: This study was funded by Sanofi (Beijing) Pharmaceutical Co, Ltd and by the Fund of The National Key Research and Development Program of China [Grant 2016YFC0905600]. CORRESPONDENCE TO: Chen Wang, MD, PhD, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, No. 2 Yinghua Dongjie, Hepingli, Beijing 100029, China; e-mail: [email protected] Copyright Ó 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2018.09.020
2 Original Research
Patients and Methods
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Study Design
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DissolVE-2 was a multicenter, observational, cross-sectional study (ChiCTR-OOC-16010187) that screened patients for eligibility between March and September 2016 in 44 major cities at 60 major hospitals with > 500 beds. These hospitals provide high-level services, medical education, and research17 in six regions (Northeast, North, East, Northwest, Southwest, and South Central China) (Fig 1A). The ratio of included hospitals in each region’s capital and noncapital cities was 1:1.
202
The study was conducted in accordance with the Declaration of Helsinki (1964), its subsequent revisions, and Chinese Good Clinical Practice guidelines. The ethics committees of all sites approved the study protocol; however, the requirement of obtaining consent for any research utilizing patients’ medical information was waived because this study was retrospective in nature. Patients and Procedures The sample size calculation is based on estimation of the prevalence of hospital-acquired VTE risk at the ward level. Assuming the lowest proportion of VTE risk ward patients to be approximately 0.03, to assess the true prevalence of VTE risk at 50% with a precision of 5%, a minimum of 402 patients had to be evaluated using the Clopper-Pearson exact method.18 Hence, the sample size was
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A
222
276
B
223
277 278
51,835 hospital patients recruited
224
279
37,835 patients found to be ineligible 32,673 violated the inclusion criteria (86.4%) 6,228 met the exclusion criteria (16.5%) 130 failed screening due to other reasons (0.3%)
225 226
280 281
227
282 14,000 eligible patients screened
228 229
283 284
391 patients did not meet the inclusion and exclusion criteria present in the full analysis set
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13,609 patients enrolled
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6,623 (48.7%) medical patients
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6,986 (51.3%) surgical patients
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Figure 1 – Selection of patient population. A, Regions and number of hospitals from that region which were chosen for the study. B, Study population and reasons for exclusion.
242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268
Patients from general medicine, cardiac, neurovascular, oncology, respiratory, rheumatic, and the general surgical and orthopedic wards were included. Patients from the following wards were excluded: psychiatric; maternity; pediatric; ear, nose, and throat; burn; dermatology; ophthalmology; chronic; rehabilitation; and palliative care. Data from eligible patients’ medical charts were collected by using an electronic case report, de-identified, and entered into an electronic data capture system by trained data management personnel. The abstracted data included demographic information, admission and discharge diagnoses, treatment/ procedural details, risk factors for bleeding and VTE present during hospitalization, and type of VTE prophylaxis administered as described in the CHEST guidelines, 9th edition.7-9 We did not use the latest guidelines (10th edition)19 because it contains updates for VTE treatment only and not prophylaxis. Adult inpatients (hospitalized for $ 72 h) from eligible wards were screened. Inclusion criteria were treatment for acute illnesses such as an infectious, cardiac, or respiratory disease, or cancer according to the CHEST guidelines, 8th and 9th editions6,7; surgery, CHEST guidelines, 9th edition8,9; or a major traumatic experience that did not require surgery. Exclusion criteria were admission for diagnostic testing, hemodialysis, same-day surgery, pregnancy, or a chronic condition; VTE treatment # 24 h of admission; or admission to an ineligible ward. VTE risk was evaluated in acute medical and surgical patients via the Padua Prediction Score or Caprini Risk Assessment model, respectively (e-Tables 1-3). The risk factors were evaluated during admission, 72 h
273 274 275
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following admission, and prior to discharge for medical patients, and during admission, 24 h following operation, and prior to discharge for surgical patients. Dynamic evaluations were further conducted if the patient’s situation changed depending on the VTE and bleeding risk. Although medical patients were classified into low or high risk, surgical patients were classified into very low, low, moderate, and high risk as defined by using the CHEST guidelines, 9th edition.7-9 Subgroup analyses of VTE risk according to disease and surgery type were also performed. Patients were categorized as high risk or not at risk of major bleeding complications according to the criteria defined in the CHEST guidelines, 9th edition. Information on bleeding events and their associated reasons were obtained from medical records. Taking VTE and major bleeding risk into account, the proportion of at-risk patients receiving CHEST-recommended prophylaxis7-9 was evaluated throughout the duration of the patients’ stay. The prophylaxis received was categorized as any VTE or appropriate prophylaxis. Appropriate prophylaxis was defined as prophylaxis compliant with the CHEST guidelines, 9th edition. The occurrence of symptomatic VTE during hospitalization was also assessed as an exploratory objective.
298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316
Statistical Analyses Continuous variables are presented as the number of observations, mean, SD, minimum, and maximum; categorical variables are presented as the number and percentage of the population. Distribution of hospitalized patients at various VTE risk levels, the prophylaxis received, and the distribution of in-hospital VTE events are summarized separately for medical and surgical patients in terms of percentage with 95% CIs. Statistical analyses were performed by using SAS version 9.4 (SAS Institute, Inc).
317 318 319 320 321 322 323 324
Results
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estimated as follows: 402/0.03 ¼ 13,400. We estimated that each center had to enroll approximately 230 patients to obtain this sample size.
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Baseline Characteristics
From the 14,000 eligible patients, 13,609 (mean age, 56.7 16.8 years; 52.6% female) were included in the full
analysis set (Fig 1B). Surgical patients (n ¼ 6,986) were mostly female (n ¼ 4,343 [62.2%]) with a mean age of 50.4 15.5 years and a BMI of 23.4 3.6 kg/m2; medical patients (n ¼ 6,623) were mostly male (n ¼ 3,811 [57.5%]) with a mean age of 63.2 15.6
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TABLE 1
Characteristic
334
Age, y
335
No.
336 337 338 339 340 341 342
] Baseline and Demographic Characteristics of the Surgical and Medical Patients
6,623
13,607
50.4 15.5
63.2 15.6
56.7 16.8
387
Total (N ¼ 13,609)
388 390 391 392
Male
2,643 (37.8%)
Female
4,343 (62.2%)
3,811 (57.5%) 2,812 (42.5%)
6,454 (47.4%)
393
7,155 (52.6%)
394 395
Weight, kg No. BMI (kg/m2)
345
No.
346
Mean SD
350
6,984
Mean SD
344
349
Medical Patients (n ¼ 6,623)
Sex
343
348
Surgical Patients (n ¼ 6,986)
396
6,321
4,870
11,191
62.4 11.6
61.7 12.5
62.1 12.0
398
4,645
3,160
7,805
400
23.4 3.6
22.8 4.0
23.1 3.8
397 399 401 402
Duration of hospitalization, d Mean SD
403 14.4 11.6
14.3 10.6
404
14.4 11.1
405
351 352 353 354 355 356 357 358
406
years and a BMI of 22.8 4.0 kg/m2. Mean duration of hospitalization was 14.4 11.1 days for the overall population, 14.4 11.6 days for surgical patients, and 14.3 10.6 days for medical patients (Table 1). Surgical patients largely underwent general and abdominal-pelvic surgery (72.7%), whereas medical patients mainly
359 360 361 362 363 364 365
TABLE 2
] Distribution of Acute Medical Disease or Surgery Type in Medical or Surgical Patients
Acute Surgery or Medical Disease Type
No. (%)
Surgical patients, n ¼ 6,986
366
General and abdominal-pelvic surgery
367
Bariatric surgery
6 (< 0.1)
368
Cardiac surgery
48 (0.7)
369
Craniotomy
342 (4.9)
370
5,077 (72.7)
Thoracic surgery
396 (5.7)
371
Vascular surgery
152 (2.2)
372
Spinal surgery
436 (6.2)
Major trauma
85 (1.2)
373 374 375 376
Orthopedic
250 (3.6)
Nonsurgical major trauma
227 (3.2)
377
Medical patients, n ¼ 6,623
378
Congestive heart failure
379
Severe respiratory disease
1,253 (18.9)
380
Active cancer
1,535 (23.2)
Acute stroke
1,451 (21.9)
383
Acute infection including sepsis
2,143 (32.4)
384
Rheumatic diseases
381 382
386
389
Mean SD
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385
4 Original Research
619 (9.3)
301 (4.5)
407
experienced acute infection (32.4%) and active cancer (23.2%) (Table 2).
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VTE Risk Stratification and Risk Factors
411
A total of 6,155 (45.2%; 95% CI, 44.4-46.0) patients from the overall population were deemed to be at high risk for VTE. Figure 2A shows that such patients were greater in the surgical group (53.4%; 95% CI, 52.2-54.6) than in the medical group (36.6%; 95% CI, 35.4-37.8). Orthopedic (100%; 95% CI, 99.8-100) and bariatric (100%; 95% CI, 91.7-100) surgery patients had the highest VTE risk among surgical patients; congestive heart failure (54.9%; 95% CI, 50.9-58.9) patients had the highest VTE risk among medical patients (e-Table 4). The major VTE risk factor in surgical patients was major open surgery (52.6%); acute infection and/or rheumatologic disorder (42.2%) was the major VTE risk factor in medical patients (Table 3). In total, 1,695 (24.3%), 1,852 (26.5%), 1,506 (21.6%), and 1,328 (19.0%) surgical patients, and 2,275 (34.3%), 1,236 (18.7%), 334 (5.0%), and 57 (0.9%) medical patients, reported carrying two to five or more VTE risk factors, respectively.
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Bleeding Risk Factors
434
A high risk of major bleeding was present in 3,472 (25.5%) patients overall (2,766 surgical patients [39.6%]; 706 medical patients [10.7%]). Major bleeding risk factors in surgical patients were concomitant use of nonsteroidal antiinflammatory drugs (13.5%) and
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441
A
442
Medical patients High risk
443
Surgical patients Low risk 13.9%
445
36.6%
446
501
Confined to bed (> 72 h)
2,140 (30.6)
503
Malignancy
1,924 (27.5)
504
Laparoscopic surgery (> 45 min)
1,658 (23.7)
Minor surgery
1,501 (21.5)
Age 61-74 y
1,495 (21.4)
18
508
BMI > 25 kg/m2
1,366 (19.6)
509
16
Gynecologic noncancer surgery
987 (14.1)
510
14
Central venous access
840 (12.0)
511
619 (8.9)
512
Age $ 75 y
450 (6.4)
514
Spinal surgery for malignant disease
431 (6.2)
Craniotomy
356 (5.1)
Orthopedics major surgery
255 (3.7)
450
32.7%
Low risk 20 % of Patients Receiving Prophylaxis
457 458 459 460 461 462 463 464 465
468 469 470 471 472 473
Medium risk 19.0%
11.8%
12 10
9.3%
8 6.0%
6 4
Medical patients
Surgical patients
Any prophylaxis Appropriate prophylactic method Figure 2 – Risk stratification and adoption of prophylaxis in medical and surgical patients. A, Proportions of medical and surgical patients at various levels of VTE risk. B, Percentage of medical and surgical patients receiving any prophylaxis or appropriate prophylactic method.
474 475 476 477 478
abdominal surgery (12.8%), whereas in medical patients, these factors were cancer (24.4%), rheumatic disease (6.1%), and age $ 85 years (6.0%) (Table 4).
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History of unexplained or recurrent spontaneous abortion
505 506 507
513 515 516 517 518 519
Medical patients, n ¼ 6,623
2 0
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467
High risk
B
456
500 502
449
455
499
Surgical patients, n ¼ 6,986
3,174 (45.4)
63.4%
454
No. (%)
Age 41-60 y
448
453
498
3,677 (52.6)
53.4%
452
497
Patients
Major open surgery (> 45 min)
447
451
496
] Common VTE Risk Factors in Hospitalized
Risk Factors
444
466
TABLE 3
Administration of VTE Prophylaxis
VTE prophylaxis was evaluated considering VTE and major bleeding risk simultaneously. Patients who were at risk but did not require prophylaxis were not excluded. Hence, 13,609 patients were included in the analysis of any prophylaxis administration. However, such patients were excluded while analyzing administration of appropriate prophylaxis. Any VTE prophylaxis was administered to 1,942 patients (14.3%; 95% CI, 13.714.9), which included 984 high-risk surgical patients (26.4%; 95% CI, 25.0-27.8) and 312 high-risk medical patients (12.9%; 95% CI, 11.5-14.2) (Table 5). From the 971 patients who received the appropriate VTE prophylactic method (10.3%; 95% CI, 9.7-10.9), 608 were high-risk surgical patients (16.3%; 95% CI,
Acute infection and/or rheumatologic disorder
2,797 (42.2)
Elderly age ($ 70 y)
2,507 (37.9)
Heart and/or respiratory failure
2,006 (30.3)
520 521 522 523 524
Reduced mobility
1,935 (29.2)
525
Active cancer
1,614 (24.4)
526
Acute myocardial infarction or ischemic stroke
1,392 (21.0)
527 528 529
Recent (# 1 mo) trauma and/or surgery
137 (2.1)
Obesity (BMI $ 30 kg/m2)
119 (1.8)
531
Ongoing hormonal treatment
21 (0.3)
532
Previous VTE (with the exclusion of superficial vein thrombosis)
18 (0.3)
Already known thrombophilic condition
530
533 534 535
4 (0.1)
536 537 538 539 540
15.1-17.5), and 146 were high-risk medical patients (6.0%; 95% CI, 5.1-7.0).
541
Figure 2B shows the overall picture of VTE prophylaxis administration in Chinese hospitals, stratified according to type of inpatient. The geographical stratification of appropriate VTE prophylaxis administration ranging from 0.8% (95% CI, 0.4-1.5) in Northeast China to 4.9% (95% CI, 4.0-6.05) in North China is shown in e-Table 5. Stratification according to inpatient type and risk level showed that appropriate prophylaxis
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551
TABLE 4
] Common Bleeding Risk Factors in Hospitalized Patients
552 553 554 555
Risk Factor
No. (%)
Surgical patients, n ¼ 6,986
556
Active gastroduodenal ulcer
557
Previous major bleeding
558 559
Significant renal impairment (GFR < 30 mL/min/m2)
560
Platelet count < 50 109/L
561
Stroke
562
Uncontrolled systemic hypertension
91 (1.3)
Concomitant use of anticoagulant agents
30 (0.4)
Concomitant use of antiplatelet therapy
75 (1.1)
567 568
Concomitant use of NSAIDs
563 564 565 566
Coagulation dysfunction
570
Abdominal surgery
572 573
230 (3.3) 99 (1.4) 21 (0.3) 228 (3.3)
569 571
57 (0.8)
Pancreaticoduodenectomy Hepatic resection
946 (13.5) 24 (0.3) 892 (12.8) 5 (0.1) 112 (1.6)
574
Cardiac surgery
40 (0.6)
575
Thoracic surgery
3 (0.04)
576
Craniotomy
365 (5.1)
577
Spinal surgery
464 (6.6)
578
Spinal trauma
108 (1.5)
579 580 581
Medical patients, n ¼ 6,623 Active gastroduodenal ulcer
60 (0.9)
Bleeding 3 mo prior to admission
139 (2.1)
583
Platelet count < 50 109/L
199 (3.0)
584
Age $ 85 y
400 (6.0)
585
316 (4.8)
586
Significant renal impairment (GFR < 30 mL/min/m2)
587
ICU/CCU admission
379 (5.7)
588
Central venous catheter use
394 (5.9)
582
589
Rheumatic disease
590
Cancer
591 592 593
402 (6.1) 1,614 (24.4)
CCU ¼ coronary care unit; GFR ¼ glomerular filtration rate; NSAID ¼ nonsteroidal antiinflammatory drug.
594 595 596 597 598 599 600 601 602 603 604 605
administration to high-risk medical and surgical patients was highest in the Northwest (4.9%; 95% CI, 2.0-9.8) and North (7.6%; 95% CI, 5.9-9.5) China, respectively. Distribution of VTE Events During Hospitalization
VTE events during hospitalization occurred in 44 inpatients overall (0.3%; 95% CI, 0.2-0.4), with the incidence for surgical (n ¼ 21) and medical (n ¼ 23) inpatients being similar (0.3%; 95% CI, 0.2-0.5). VTE events occurred more frequently in the high-risk VTE
6 Original Research
group than in the low- to moderate-risk groups for both medical (0.7% [95% CI, 0.4-1.1] vs 0.2% [95% CI, 0.1-0.3]) and surgical (0.5% [95% CI, 0.3-0.8] vs < 0.1% [95% CI, 0.0-0.2]) inpatients. None of the patients receiving appropriate VTE prevention measures experienced VTE events.
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Discussion To our knowledge, this analysis is the first multicenter study to systematically investigate the current real-world status of VTE risk levels and prophylaxis in hospitalized Chinese patients. We found that the majority of admitted surgical and medical patients were at risk of VTE. Furthermore, many of these patients did not receive CHEST-recommended7-9 VTE prophylaxis, thus illustrating a large real-world gap between mostly Western consensus evidence-based guidelines and current Chinese clinical practice. A key difference exists between ENDORSE —a large, multinational, observational study assessing VTE risk and its prophylaxis in hospitalized patients—and the present study. ENDORSE used CHEST, 7th edition,20 guidelines (which evaluated VTE risk utilizing disease or surgical factors), whereas the present study used CHEST, 9th edition,7-9 guidelines (which recommended the Caprini and Padua models for VTE risk evaluation). Utilization of modern methods in our study may have increased the accuracy of risk detection compared with ENDORSE.11 Moreover, because ENDORSE excluded China (approximately 20% of the world’s population), our findings might fill the gap left by ENDORSE. We also identified a unique profile of VTE risk factors such as major surgery (52.6%) in surgical patients and acute infection and/or rheumatologic disorder (42.2%) in medical patients. Overall, 58.9% of patients had > 2 VTE risk factors. In contrast, the ENDORSE study reported chronic pulmonary disease, chronic heart failure, and obesity at the time of hospitalization, and immobilization during hospitalization, to be the most frequent risk factors in both medical and surgical patients. These differences may have occurred largely due to variations in profiles and races. Moreover, ENDORSE evaluated inpatients from a particular ward/floor only on a single day, which might have precluded accurate estimation of VTE risk factors. Interestingly, despite the distinct eligible populations, the RAMP study,16 in concordance with our findings, reported that 57.3% of Chinese ICU/ CCU patients had $ 2 VTE risk factors. 11
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Any prophylaxis administration (19.0% vs 9.3%) was probably higher in surgical patients than in medical
[
614
660
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661
TABLE 5
] Proportion of Hospitalized Patients With Any VTE Risk Receiving Different Types of VTE Prophylaxis
662 663 664 665 666
Any Prophylaxis, No./Na (%; 95% CI)
VTE Risk Surgical and medical patients Surgical patients
Q15
717
Appropriate Prophylactic Method, No./Nb (%; 95% CI)
1,942/13,609 (14.3; 13.7-14.9)
971/9,411 (10.3; 9.7-10.9)
1,326/6,986 (19.0; 18.1-19.9)
825/6,986 (11.8; 11.0-12.6)
.
.
716 718 719 720 721
667
Very low
668
Low
44/971 (4.5; 3.2-5.9)
18/971 (1.9; 1.0-2.8)
723
669
Moderate
298/2,285 (13.0; 11.6-14.4)
199/2,285 (8.7; 7.5-9.9)
724
670
High
984/3,730 (26.4; 25.0-27.8)
608/3,730 (16.3; 15.1-17.5)
725 726
671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715
Medical patients
616/6,623 (9.3; 8.65-10.0)
146/2,425 (6.0; 5.1-7.0)
Low
304/4,198 (7.2; 6.4-8.0)
.
High
312/2,425 (12.9; 11.5-14.2)
146/2,425 (6.0; 5.1-7.0)
722
727 728 729
No. ¼ number of patients who received the prophylaxis; Na ¼ number of patients who had any VTE risk; Nb ¼ number of patients who needed to receive appropriate prophylaxis as per the CHEST guidelines, 9th edition (among surgical patients, all other patients except those at a very low risk needed to receive prophylaxis; among medical patients, only high-risk patients needed to receive prophylaxis).
patients because research has shown a higher risk of VTE in patients undergoing surgery.21 Furthermore, any type of prophylaxis was administered to orthopedic surgery patients the most (66.4%), probably because they have the highest risk of VTE,22 and orthopedists are highly aware of VTE prevention. At-risk patients in ENDORSE received nearly five times more CHEST-recommended prophylaxis than those in DissolVE-2 (50.2% vs 10.3%). Furthermore, the implementation of appropriate prophylaxis (3.6%) was far lower than previous observations.23,24 In Canada, approximately 16% of acutely ill patients received appropriate prophylaxis,25 whereas in the Venous Thromboembolism Prophylaxis in Intensive Care Unit Patients (VOICE) study, 31.2% of patients received pharmacologic treatment and 44.2% received a combination of pharmacologic and mechanical prophylaxis.22 The disparity in CHEST-recommended prophylaxis between DissolVE-2 and other studies could have occurred because we stringently defined “CHESTrecommended prophylaxis,” after considering key elements in a prophylaxis course such as initiation time, modalities, and duration. 11
Only 14.3% of at-risk patients received some form of prophylaxis, with approximately 10.3% receiving the “correct’’ prophylactic method. The trend of appropriate prophylaxis being administered to at-risk patients was observed even after geographical stratification, suggesting physicians across China are like-minded. These implementation rates suggest that physicians are aware of VTE risks but often do not comply with guideline recommendations, probably due to lack of medical education and enforcement or due to genuine concerns regarding the relevance of foreign guidelines to Chinese patients.
Estimating the distribution of VTE events during hospitalization was our exploratory objective. The incidence of in-hospital VTE reported in the present study (0.3%) is higher than values reported in the United Kingdom (0.21% in 2010 to 0.14% in 2016)26 but similar to that of the United States (0.3%).27 These findings imply that the current VTE prevention strategies are far less than optimal and also have some crucial implications for health-care resource planning. The results of DissolVE-2 may be of significance from several perspectives. The gap between recommended and administered VTE prophylaxis can garner attention from both practitioners and hospital management, leading to enhanced medical education regarding inhospital VTE prophylaxis and interventions to make VTE risk-assessment systems at the ward or hospital level mandatory. Chinese local academic associations can also consider and revise their guidelines or consensus based on the current data. From the national health-care perspective, DissolVE-2 will contribute significant insights to the decision-making capabilities of the current health-care system in China, as well as reinforce action regarding resource planning because it can be an important reference to prospectively study the burden of thrombosis and bleeding risk associated with prophylaxis or its absence. There are a few limitations in our study. DissolVE-2 was conducted retrospectively and hence was unable to determine causal inferences between VTE risk level and obtaining appropriate prophylaxis. Moreover, patient chart data instead of interview data were used, which could have caused some inaccuracies in obtaining the latest information. The hospitals chosen for this study
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represented the best care available in China and thus might not depict the general level of care given. Considering China’s population density, there was a positive skew toward the inclusion of hospitals from South and East China compared with the Northwestern region. Moreover, patient data from several provinces were lacking, which if added, might potentially change the results. Bleeding risk factors were analyzed for the whole cohort and not after stratifying the patients on the basis of VTE risk. Hence, we cannot interpret the risk factors based on the risk level.
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Conclusions The DissolVE-2 study provided a nationwide perspective on the real-world clinical practice of VTE risk assessment and prophylaxis implementation in China. It showed that although a considerable proportion of medical and surgical patients are at risk of VTE, implementation of VTE prophylaxis is low, especially in medical patients. Furthermore, these findings highlight the need for greater awareness and actions from both physicians and the government to tackle the growing burden of VTE.
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Acknowledgments
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Author contributions: C. W. is the guarantor of the article and takes responsibility for the content of the manuscript, including integrity of the data and accuracy of the analysis. Z. G. Z. and C. W. conceptualized and designed the study. Z. G. Z., X. Y. Q., Y. K. S., R. H. X., W. M. L., Q. C. K., J. M. Q., Z. Z., and C. W. participated in data acquisition; Z. G. Z., Z. Z., and C. W. analyzed and interpreted the data; and Z. G. Z., Z. Z., and C. W. drafted the manuscript. All authors provided final approval of the version to be published.
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Financial/nonfinancial disclosures: The authors have reported to CHEST the following: All the authors declare support from Sanofi for the submitted work. C. W., Z. G. Z., X. Y. Q., Y. K. S., R. H. X., W. M. L., Q. C. K., Y. M. X., and J. M. Q. were members of the DissolVE steering committee. Z. G. Z., X. Y. Q., Y. K. S., R. H. X., W. M. L., Q. C. K., J. M. Q., Y. M. X., and C. W. have received consultancy fees and clinical research funding from Sanofi. None declared: (Z. Z.).
787 788 789 790
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Role of the sponsors: This study was funded by Sanofi, and editorial support in the preparation of this publication was provided by Sanofi. The authors individually and collectively are responsible for all content and editorial decisions and received no payment from Sanofi related to the development/ presentation of this publication.
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Other contributions: The authors thank Bruce Davidson and Alexander T. Cohen for their valuable suggestions on the design of the study and revision of the manuscript. They also thank Leo J. Philip Tharappel and Amit Bhat (Indegene Pvt Ltd) for providing editorial support for the development of the manuscript.
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Data sharing: Qualified researchers may request access to patient-level data and related study documents, including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient-level data will be anonymized and study documents will be redacted to protect the privacy of our trial participants. Further details on Sanofi’s data-
8 Original Research
sharing criteria, eligible studies, and process for requesting access can be found at: https:// www.clinicalstudydatarequest.com/. Additional information: The e-Tables can be found in the Supplemental Materials section of the online article.
References 1. Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med. 1999;341(11):793-800. 2. Cheuk BL, Cheung GC, Cheng SW. Epidemiology of venous thromboembolism in a Chinese population. Br J Surg. 2004;91(4):424-428. 3. Law Y, Chan YC, Cheng SW. Epidemiological updates of venous thromboembolism in a Chinese population. Asian J Surg. 2018;41(2): 176-182. 4. Karande GY, Hedgire SS, Sanchez Y, et al. Advanced imaging in acute and chronic deep vein thrombosis. Cardiovasc Diagn Ther. 2016;6(6):493-507. 5. Smith SB, Geske JB, Maguire JM, Zane NA, Carter RE, Morgenthaler TI. Early anticoagulation is associated with reduced mortality for acute pulmonary embolism. Chest. 2010;137(6):1382-1390. 6. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(suppl 6):381S-453S. 7. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2): e195S-e226S. 8. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2): e227S-e277S.
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9. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2): e278S-e325S. 10. Liew NC, Alemany GV, Angchaisuksiri P, et al. Asian venous thromboembolism guidelines: updated recommendations for the prevention of venous thromboembolism. Int Angiol J Int Union Angiol. 2017;36(1):1-20. 11. Cohen AT, Tapson VF, Bergmann JF, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet Lond Engl. 2008;371(9610):387-394. 12. Alsayegh F, Kamaliddin H, Sheshah E, Bukhamseen N, Alkhuwaitir T, Elhoufi A. Assessment of venous thromboembolism risk and adequacy of prophylaxis in selected acute care medical centres in Arabian Gulf states: results from the ENDORSE Study. Med Princ Pract Int J Kuwait Univ Health Sci Cent. 2012;21(6): 522-528. 13. Pinjala R; ENDORSE-India Investigators. Venous thromboembolism risk & prophylaxis in the acute hospital care setting (ENDORSE), a multinational cross-sectional study: results from the Indian subset data. Indian J Med Res. 2012;136(1):60-67. 14. Ongen G, Yılmaz A, Cirak AK, et al. Venous thromboembolism risk and thromboprophylaxis among hospitalized patients: data from the Turkish arm of the ENDORSE study. Clin Appl Thromb Hemost. 2011;17(5):539-545. 15. Statistical Communique on the Development of Health and Family Planning in China in 2016. http://www. nhfpc.gov.cn/guihuaxxs/s10748/201708/ d82fa7141696407abb4ef764f3edf095. shtml. Accessed November 23, 2017.
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16. Ge J, Li Y, Jin X, Zhou J. Venous thromboembolism risk assessment and thromboprophylaxis among hospitalized
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acute medical patients in China—the RAMP study. Thromb Res. 2010;126(4): 270-275.
Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(suppl 3):338S400S.
17. Chen S. What’s Up, Daifu? Navigating the Chinese Public Hospital System. https:// www.thebeijinger.com/blog/2015/09/18/ whats-daifu-navigating-chinese-publichospital-system. Accessed November 2, 2017.
21. Seddighzadeh A, Zurawska U, Shetty R, Goldhaber SZ. Venous thromboembolism in patients undergoing surgery: low rates of prophylaxis and high rates of filter insertion. Thromb Haemost. 2007;98(6): 1220-1225.
18. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika. 1934;26(4):404-413.
22. Cionac Florescu S, Anastase DM, Munteanu AM, Stoica IC, Antonescu D. Venous thromboembolism following major orthopedic surgery. Maedica. 2013;8(2):189-194.
19. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352. 20. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on
23. Parikh KC, Oh D, Sittipunt C, et al. Venous thromboembolism prophylaxis in medical ICU patients in Asia (VOICE Asia): a multicenter, observational, crosssectional study. Thromb Res. 2012;129(4): e152-e158.
24. Ansari K, Dalal K, Patel M. Risk stratification and utilisation of thromboembolism prophylaxis in a medicalsurgical ICU: a hospital-based study. J Indian Med Assoc. 2007;105(9). 536, 538, 540 passim. 25. Kahn SR, Panju A, Geerts W, et al. Multicenter evaluation of the use of venous thromboembolism prophylaxis in acutely ill medical patients in Canada. Thromb Res. 2007;119(2):145-155. 26. Rowswell HR, Nokes TJ. Significant reduction in hospital-acquired thrombosis: impact of national risk assessment and real-time feedback. Open Heart. 2017;4(2):e000653. 27. Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb Thrombolysis. 2016;41(1):3-14.
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Venous Thromboembolism Risk Profiles and Prophylaxis in Medical and Surgical Inpatients
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The Identification of Chinese Hospitalized Patients’ Risk Profile for Venous Thromboembolism (DissolVE-2)—A Cross-sectional Study
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Zhen-guo Zhai, MD, PhD; Quan-cheng Kan, MD; Wei-min Li, MD, PhD; Xin-yu Qin, MD; Jie-ming Qu, MD, PhD;
Q1
Yuan-kai Shi, MD, PhD; Rui-hua Xu, MD, PhD; Yu-ming Xu, MD; Zhu Zhang, MD; Chen Wang, MD, PhD; on behalf of the DissolVE-2 investigators
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Limited data exist on VTE risk and prophylaxis in Chinese inpatients. The Identification of Chinese Hospitalized Patients’ Risk Profile for Venous Thromboembolism-2 (DissolVE-2), a nationwide, multicenter, cross-sectional study, was therefore designed to investigate prevalence of VTE risks and evaluate VTE prophylaxis implementation compliant with the latest prophylaxis guidelines (American College of Chest Physicians [CHEST], 9th edition).
28
METHODS:
BACKGROUND:
22 23 24 25 26
Adults admitted ($ 72 h) to 60 urban, tertiary Chinese hospitals due to acute medical conditions or surgery from March to September 2016 were assessed for VTE risk. Risk assessments were made by using the Padua Prediction Scoring or Caprini Risk Assessment model, risk factors, and prophylaxis based on the CHEST guidelines, 9th edition.
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A large proportion of hospitalized patients reported VTE risk and low rate of CHEST-recommended prophylaxis. The data highlight the insufficient management of VTE risk and show the great potential for improving physicians’ awareness and current practices across China.
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TRIAL REGISTRY:
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KEY WORDS:
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CONCLUSIONS:
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A total of 13,609 patients (6,986 surgical and 6,623 medical) were analyzed. VTE risk in surgical inpatients was categorized as low (13.9%; 95% CI, 13.1-14.7), moderate (32.7%; 95% CI, 31.6-33.8), and high (53.4%; 95% CI, 52.2-54.6); risk in medical patients was categorized as low (63.4%; 95% CI, 62.2-64.6) and high (36.6%; 95% CI, 35.4-37.8). Major risk factors in surgical and medical patients were major open surgery (52.6%) and acute infection (42.2%), respectively. Overall rate of any prophylaxis and appropriate prophylactic method was 14.3% (19.0% vs 9.3%) and 10.3% (11.8% vs 6.0%) in surgical and medical patients. RESULTS:
33
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ChiCTR-OOC-16010187.
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China; prophylaxis; risk profile; VTE
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50 ABBREVIATIONS:
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CCU = coronary care unit; CHEST = American College of Chest Physicians AFFILIATIONS: From the Department of Pulmonary and Critical Care Medicine (Drs Zhai, Zhang, and Wang), Center of Respiratory Medicine, China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, No. 2 Yinghua Dongjie, Hepingli, Beijing, China; Department of Pharmacy (Dr Kan), The First Affiliated
Hospital of Zhengzhou University, Henan, China; Department of Pulmonary and Critical Care Medicine (Dr Li), West China Hospital, Sichuan University, Sichuan, China; Department of General Surgery (Dr Qin), Zhongshan Hospital, Fudan University, Shanghai, China; Department of Respiratory Medicine (Dr Qu), Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Department of Respiratory Medicine (Dr Qu), Huadong Hospital
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VTE affects approximately 5% to 15% of patients hospitalized for medical or surgical symptoms.1 The incidence of DVT and pulmonary embolism in the Chinese population (Hong Kong) is estimated to have increased from 17.1 and 3.9, respectively, per 100,000 in 2000 to 20012 to 30.0 and 8.7 per 100,000 in 2010 to 2011.3 This approximate doubling in incidence is probably due to multiple factors, including lifestyle changes, longer life span, heightened VTE awareness, and advances in imaging availability and expertise.3,4
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Although early VTE prophylaxis is recommended,5-10 it is reportedly clinically underutilized.11 The multicenter Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting (ENDORSE) study reported that 51.8% of hospitalized patients were at risk of VTE, with only one half of those receiving prophylaxis complying with the American College of Chest Physicians (CHEST) guidelines, 7th edition. Although ENDORSE excluded China and Japan, other Asian ENDORSE substudies reported a VTE risk similar to that of the global population (50.4%). However, CHESTadherent VTE prophylaxis was lower than the overall average (32.1%).12-14
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In 2016, there were, on average, 6,321,000 medical and surgical inpatients in China on a daily basis15 at risk for hospital-acquired VTE. Concern with their
VTE-related risk and management should take into account their thrombosis and bleeding risk profiles and frequency of VTE prophylaxis administration, none of which, to the best of our knowledge, has been studied in detail. The VTE Risk Assessment and Thromboprophylaxis Among Hospitalized Acute Medical Patients in China (RAMP) study16 included ICU and coronary care unit (CCU) patients and showed that the proportion of at-risk patients in China was 57.3%. In addition, only 20.2% of these patients received CHEST-recommended VTE prophylaxis (CCU patients, 22.7%; ICU patients, 16.9%; P ¼ .0117). However, this study omitted nonICU inpatients and reported on 1,247 patients, approximately 0.02% of China’s current daily inpatient census. To understand VTE’s real-world scenario in China, a nationally representative study was required. We therefore designed and conducted the Identification of Chinese Hospitalized Patients’ Risk Profile for Venous Thromboembolism-2 (DissolVE-2) study to identify VTE and bleeding risk factors, estimate the proportions of at-risk hospitalized patients, and report the proportions receiving CHEST-compliant VTE prophylaxis in a large sample of medical and surgical inpatients. DissolVE-2 further evaluated VTE risk by using a combination of risk factor evaluation and prevalent contemporary risk-assessment modeling to facilitate comparisons with survey results from elsewhere.
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affiliated to Fudan University, Shanghai, China; Department of Medical Oncology (Dr Shi), National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Department of Medical Oncology (Dr R. H. Xu), Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong, China; Department of Neurology (Dr Y. M. Xu), The First Affiliated Hospital of Zhengzhou University, Henan, China; Peking Union Medical College (Drs Wang and Zhang), Chinese Academy of Medical Sciences, Beijing, China; and Department of Respiratory Medicine (Dr Wang), Capital Medical University, Beijing, China. A poster reporting this work was presented at the 2018 American Thoracic Society Conference, May 18-23, 2018, San Diego, CA. Drs Zhai and Zhang contributed equally. FUNDING/SUPPORT: This study was funded by Sanofi (Beijing) Pharmaceutical Co, Ltd and by the Fund of The National Key Research and Development Program of China [Grant 2016YFC0905600]. CORRESPONDENCE TO: Chen Wang, MD, PhD, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, No. 2 Yinghua Dongjie, Hepingli, Beijing 100029, China; e-mail: [email protected] Copyright Ó 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2018.09.020
2 Original Research
Patients and Methods
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Study Design
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DissolVE-2 was a multicenter, observational, cross-sectional study (ChiCTR-OOC-16010187) that screened patients for eligibility between March and September 2016 in 44 major cities at 60 major hospitals with > 500 beds. These hospitals provide high-level services, medical education, and research17 in six regions (Northeast, North, East, Northwest, Southwest, and South Central China) (Fig 1A). The ratio of included hospitals in each region’s capital and noncapital cities was 1:1.
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The study was conducted in accordance with the Declaration of Helsinki (1964), its subsequent revisions, and Chinese Good Clinical Practice guidelines. The ethics committees of all sites approved the study protocol; however, the requirement of obtaining consent for any research utilizing patients’ medical information was waived because this study was retrospective in nature. Patients and Procedures The sample size calculation is based on estimation of the prevalence of hospital-acquired VTE risk at the ward level. Assuming the lowest proportion of VTE risk ward patients to be approximately 0.03, to assess the true prevalence of VTE risk at 50% with a precision of 5%, a minimum of 402 patients had to be evaluated using the Clopper-Pearson exact method.18 Hence, the sample size was
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51,835 hospital patients recruited
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37,835 patients found to be ineligible 32,673 violated the inclusion criteria (86.4%) 6,228 met the exclusion criteria (16.5%) 130 failed screening due to other reasons (0.3%)
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391 patients did not meet the inclusion and exclusion criteria present in the full analysis set
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13,609 patients enrolled
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6,623 (48.7%) medical patients
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Figure 1 – Selection of patient population. A, Regions and number of hospitals from that region which were chosen for the study. B, Study population and reasons for exclusion.
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Patients from general medicine, cardiac, neurovascular, oncology, respiratory, rheumatic, and the general surgical and orthopedic wards were included. Patients from the following wards were excluded: psychiatric; maternity; pediatric; ear, nose, and throat; burn; dermatology; ophthalmology; chronic; rehabilitation; and palliative care. Data from eligible patients’ medical charts were collected by using an electronic case report, de-identified, and entered into an electronic data capture system by trained data management personnel. The abstracted data included demographic information, admission and discharge diagnoses, treatment/ procedural details, risk factors for bleeding and VTE present during hospitalization, and type of VTE prophylaxis administered as described in the CHEST guidelines, 9th edition.7-9 We did not use the latest guidelines (10th edition)19 because it contains updates for VTE treatment only and not prophylaxis. Adult inpatients (hospitalized for $ 72 h) from eligible wards were screened. Inclusion criteria were treatment for acute illnesses such as an infectious, cardiac, or respiratory disease, or cancer according to the CHEST guidelines, 8th and 9th editions6,7; surgery, CHEST guidelines, 9th edition8,9; or a major traumatic experience that did not require surgery. Exclusion criteria were admission for diagnostic testing, hemodialysis, same-day surgery, pregnancy, or a chronic condition; VTE treatment # 24 h of admission; or admission to an ineligible ward. VTE risk was evaluated in acute medical and surgical patients via the Padua Prediction Score or Caprini Risk Assessment model, respectively (e-Tables 1-3). The risk factors were evaluated during admission, 72 h
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following admission, and prior to discharge for medical patients, and during admission, 24 h following operation, and prior to discharge for surgical patients. Dynamic evaluations were further conducted if the patient’s situation changed depending on the VTE and bleeding risk. Although medical patients were classified into low or high risk, surgical patients were classified into very low, low, moderate, and high risk as defined by using the CHEST guidelines, 9th edition.7-9 Subgroup analyses of VTE risk according to disease and surgery type were also performed. Patients were categorized as high risk or not at risk of major bleeding complications according to the criteria defined in the CHEST guidelines, 9th edition. Information on bleeding events and their associated reasons were obtained from medical records. Taking VTE and major bleeding risk into account, the proportion of at-risk patients receiving CHEST-recommended prophylaxis7-9 was evaluated throughout the duration of the patients’ stay. The prophylaxis received was categorized as any VTE or appropriate prophylaxis. Appropriate prophylaxis was defined as prophylaxis compliant with the CHEST guidelines, 9th edition. The occurrence of symptomatic VTE during hospitalization was also assessed as an exploratory objective.
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Statistical Analyses Continuous variables are presented as the number of observations, mean, SD, minimum, and maximum; categorical variables are presented as the number and percentage of the population. Distribution of hospitalized patients at various VTE risk levels, the prophylaxis received, and the distribution of in-hospital VTE events are summarized separately for medical and surgical patients in terms of percentage with 95% CIs. Statistical analyses were performed by using SAS version 9.4 (SAS Institute, Inc).
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Results
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estimated as follows: 402/0.03 ¼ 13,400. We estimated that each center had to enroll approximately 230 patients to obtain this sample size.
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Baseline Characteristics
From the 14,000 eligible patients, 13,609 (mean age, 56.7 16.8 years; 52.6% female) were included in the full
analysis set (Fig 1B). Surgical patients (n ¼ 6,986) were mostly female (n ¼ 4,343 [62.2%]) with a mean age of 50.4 15.5 years and a BMI of 23.4 3.6 kg/m2; medical patients (n ¼ 6,623) were mostly male (n ¼ 3,811 [57.5%]) with a mean age of 63.2 15.6
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325 326 327 328 329 330
331 332 333
TABLE 1
Characteristic
334
Age, y
335
No.
336 337 338 339 340 341 342
] Baseline and Demographic Characteristics of the Surgical and Medical Patients
6,623
13,607
50.4 15.5
63.2 15.6
56.7 16.8
387
Total (N ¼ 13,609)
388 390 391 392
Male
2,643 (37.8%)
Female
4,343 (62.2%)
3,811 (57.5%) 2,812 (42.5%)
6,454 (47.4%)
393
7,155 (52.6%)
394 395
Weight, kg No. BMI (kg/m2)
345
No.
346
Mean SD
350
6,984
Mean SD
344
349
Medical Patients (n ¼ 6,623)
Sex
343
348
Surgical Patients (n ¼ 6,986)
396
6,321
4,870
11,191
62.4 11.6
61.7 12.5
62.1 12.0
398
4,645
3,160
7,805
400
23.4 3.6
22.8 4.0
23.1 3.8
397 399 401 402
Duration of hospitalization, d Mean SD
403 14.4 11.6
14.3 10.6
404
14.4 11.1
405
351 352 353 354 355 356 357 358
406
years and a BMI of 22.8 4.0 kg/m2. Mean duration of hospitalization was 14.4 11.1 days for the overall population, 14.4 11.6 days for surgical patients, and 14.3 10.6 days for medical patients (Table 1). Surgical patients largely underwent general and abdominal-pelvic surgery (72.7%), whereas medical patients mainly
359 360 361 362 363 364 365
TABLE 2
] Distribution of Acute Medical Disease or Surgery Type in Medical or Surgical Patients
Acute Surgery or Medical Disease Type
No. (%)
Surgical patients, n ¼ 6,986
366
General and abdominal-pelvic surgery
367
Bariatric surgery
6 (< 0.1)
368
Cardiac surgery
48 (0.7)
369
Craniotomy
342 (4.9)
370
5,077 (72.7)
Thoracic surgery
396 (5.7)
371
Vascular surgery
152 (2.2)
372
Spinal surgery
436 (6.2)
Major trauma
85 (1.2)
373 374 375 376
Orthopedic
250 (3.6)
Nonsurgical major trauma
227 (3.2)
377
Medical patients, n ¼ 6,623
378
Congestive heart failure
379
Severe respiratory disease
1,253 (18.9)
380
Active cancer
1,535 (23.2)
Acute stroke
1,451 (21.9)
383
Acute infection including sepsis
2,143 (32.4)
384
Rheumatic diseases
381 382
386
389
Mean SD
347
Q14
385
4 Original Research
619 (9.3)
301 (4.5)
407
experienced acute infection (32.4%) and active cancer (23.2%) (Table 2).
408 409 410
VTE Risk Stratification and Risk Factors
411
A total of 6,155 (45.2%; 95% CI, 44.4-46.0) patients from the overall population were deemed to be at high risk for VTE. Figure 2A shows that such patients were greater in the surgical group (53.4%; 95% CI, 52.2-54.6) than in the medical group (36.6%; 95% CI, 35.4-37.8). Orthopedic (100%; 95% CI, 99.8-100) and bariatric (100%; 95% CI, 91.7-100) surgery patients had the highest VTE risk among surgical patients; congestive heart failure (54.9%; 95% CI, 50.9-58.9) patients had the highest VTE risk among medical patients (e-Table 4). The major VTE risk factor in surgical patients was major open surgery (52.6%); acute infection and/or rheumatologic disorder (42.2%) was the major VTE risk factor in medical patients (Table 3). In total, 1,695 (24.3%), 1,852 (26.5%), 1,506 (21.6%), and 1,328 (19.0%) surgical patients, and 2,275 (34.3%), 1,236 (18.7%), 334 (5.0%), and 57 (0.9%) medical patients, reported carrying two to five or more VTE risk factors, respectively.
412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433
Bleeding Risk Factors
434
A high risk of major bleeding was present in 3,472 (25.5%) patients overall (2,766 surgical patients [39.6%]; 706 medical patients [10.7%]). Major bleeding risk factors in surgical patients were concomitant use of nonsteroidal antiinflammatory drugs (13.5%) and
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435 436 437 438 439 440
441
A
442
Medical patients High risk
443
Surgical patients Low risk 13.9%
445
36.6%
446
501
Confined to bed (> 72 h)
2,140 (30.6)
503
Malignancy
1,924 (27.5)
504
Laparoscopic surgery (> 45 min)
1,658 (23.7)
Minor surgery
1,501 (21.5)
Age 61-74 y
1,495 (21.4)
18
508
BMI > 25 kg/m2
1,366 (19.6)
509
16
Gynecologic noncancer surgery
987 (14.1)
510
14
Central venous access
840 (12.0)
511
619 (8.9)
512
Age $ 75 y
450 (6.4)
514
Spinal surgery for malignant disease
431 (6.2)
Craniotomy
356 (5.1)
Orthopedics major surgery
255 (3.7)
450
32.7%
Low risk 20 % of Patients Receiving Prophylaxis
457 458 459 460 461 462 463 464 465
468 469 470 471 472 473
Medium risk 19.0%
11.8%
12 10
9.3%
8 6.0%
6 4
Medical patients
Surgical patients
Any prophylaxis Appropriate prophylactic method Figure 2 – Risk stratification and adoption of prophylaxis in medical and surgical patients. A, Proportions of medical and surgical patients at various levels of VTE risk. B, Percentage of medical and surgical patients receiving any prophylaxis or appropriate prophylactic method.
474 475 476 477 478
abdominal surgery (12.8%), whereas in medical patients, these factors were cancer (24.4%), rheumatic disease (6.1%), and age $ 85 years (6.0%) (Table 4).
479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495
History of unexplained or recurrent spontaneous abortion
505 506 507
513 515 516 517 518 519
Medical patients, n ¼ 6,623
2 0
print & web 4C=FPO
467
High risk
B
456
500 502
449
455
499
Surgical patients, n ¼ 6,986
3,174 (45.4)
63.4%
454
No. (%)
Age 41-60 y
448
453
498
3,677 (52.6)
53.4%
452
497
Patients
Major open surgery (> 45 min)
447
451
496
] Common VTE Risk Factors in Hospitalized
Risk Factors
444
466
TABLE 3
Administration of VTE Prophylaxis
VTE prophylaxis was evaluated considering VTE and major bleeding risk simultaneously. Patients who were at risk but did not require prophylaxis were not excluded. Hence, 13,609 patients were included in the analysis of any prophylaxis administration. However, such patients were excluded while analyzing administration of appropriate prophylaxis. Any VTE prophylaxis was administered to 1,942 patients (14.3%; 95% CI, 13.714.9), which included 984 high-risk surgical patients (26.4%; 95% CI, 25.0-27.8) and 312 high-risk medical patients (12.9%; 95% CI, 11.5-14.2) (Table 5). From the 971 patients who received the appropriate VTE prophylactic method (10.3%; 95% CI, 9.7-10.9), 608 were high-risk surgical patients (16.3%; 95% CI,
Acute infection and/or rheumatologic disorder
2,797 (42.2)
Elderly age ($ 70 y)
2,507 (37.9)
Heart and/or respiratory failure
2,006 (30.3)
520 521 522 523 524
Reduced mobility
1,935 (29.2)
525
Active cancer
1,614 (24.4)
526
Acute myocardial infarction or ischemic stroke
1,392 (21.0)
527 528 529
Recent (# 1 mo) trauma and/or surgery
137 (2.1)
Obesity (BMI $ 30 kg/m2)
119 (1.8)
531
Ongoing hormonal treatment
21 (0.3)
532
Previous VTE (with the exclusion of superficial vein thrombosis)
18 (0.3)
Already known thrombophilic condition
530
533 534 535
4 (0.1)
536 537 538 539 540
15.1-17.5), and 146 were high-risk medical patients (6.0%; 95% CI, 5.1-7.0).
541
Figure 2B shows the overall picture of VTE prophylaxis administration in Chinese hospitals, stratified according to type of inpatient. The geographical stratification of appropriate VTE prophylaxis administration ranging from 0.8% (95% CI, 0.4-1.5) in Northeast China to 4.9% (95% CI, 4.0-6.05) in North China is shown in e-Table 5. Stratification according to inpatient type and risk level showed that appropriate prophylaxis
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542 543 544 545 546 547 548 549 550
551
TABLE 4
] Common Bleeding Risk Factors in Hospitalized Patients
552 553 554 555
Risk Factor
No. (%)
Surgical patients, n ¼ 6,986
556
Active gastroduodenal ulcer
557
Previous major bleeding
558 559
Significant renal impairment (GFR < 30 mL/min/m2)
560
Platelet count < 50 109/L
561
Stroke
562
Uncontrolled systemic hypertension
91 (1.3)
Concomitant use of anticoagulant agents
30 (0.4)
Concomitant use of antiplatelet therapy
75 (1.1)
567 568
Concomitant use of NSAIDs
563 564 565 566
Coagulation dysfunction
570
Abdominal surgery
572 573
230 (3.3) 99 (1.4) 21 (0.3) 228 (3.3)
569 571
57 (0.8)
Pancreaticoduodenectomy Hepatic resection
946 (13.5) 24 (0.3) 892 (12.8) 5 (0.1) 112 (1.6)
574
Cardiac surgery
40 (0.6)
575
Thoracic surgery
3 (0.04)
576
Craniotomy
365 (5.1)
577
Spinal surgery
464 (6.6)
578
Spinal trauma
108 (1.5)
579 580 581
Medical patients, n ¼ 6,623 Active gastroduodenal ulcer
60 (0.9)
Bleeding 3 mo prior to admission
139 (2.1)
583
Platelet count < 50 109/L
199 (3.0)
584
Age $ 85 y
400 (6.0)
585
316 (4.8)
586
Significant renal impairment (GFR < 30 mL/min/m2)
587
ICU/CCU admission
379 (5.7)
588
Central venous catheter use
394 (5.9)
582
589
Rheumatic disease
590
Cancer
591 592 593
402 (6.1) 1,614 (24.4)
CCU ¼ coronary care unit; GFR ¼ glomerular filtration rate; NSAID ¼ nonsteroidal antiinflammatory drug.
594 595 596 597 598 599 600 601 602 603 604 605
administration to high-risk medical and surgical patients was highest in the Northwest (4.9%; 95% CI, 2.0-9.8) and North (7.6%; 95% CI, 5.9-9.5) China, respectively. Distribution of VTE Events During Hospitalization
VTE events during hospitalization occurred in 44 inpatients overall (0.3%; 95% CI, 0.2-0.4), with the incidence for surgical (n ¼ 21) and medical (n ¼ 23) inpatients being similar (0.3%; 95% CI, 0.2-0.5). VTE events occurred more frequently in the high-risk VTE
6 Original Research
group than in the low- to moderate-risk groups for both medical (0.7% [95% CI, 0.4-1.1] vs 0.2% [95% CI, 0.1-0.3]) and surgical (0.5% [95% CI, 0.3-0.8] vs < 0.1% [95% CI, 0.0-0.2]) inpatients. None of the patients receiving appropriate VTE prevention measures experienced VTE events.
606 607 608 609 610 611 612 613
Discussion To our knowledge, this analysis is the first multicenter study to systematically investigate the current real-world status of VTE risk levels and prophylaxis in hospitalized Chinese patients. We found that the majority of admitted surgical and medical patients were at risk of VTE. Furthermore, many of these patients did not receive CHEST-recommended7-9 VTE prophylaxis, thus illustrating a large real-world gap between mostly Western consensus evidence-based guidelines and current Chinese clinical practice. A key difference exists between ENDORSE —a large, multinational, observational study assessing VTE risk and its prophylaxis in hospitalized patients—and the present study. ENDORSE used CHEST, 7th edition,20 guidelines (which evaluated VTE risk utilizing disease or surgical factors), whereas the present study used CHEST, 9th edition,7-9 guidelines (which recommended the Caprini and Padua models for VTE risk evaluation). Utilization of modern methods in our study may have increased the accuracy of risk detection compared with ENDORSE.11 Moreover, because ENDORSE excluded China (approximately 20% of the world’s population), our findings might fill the gap left by ENDORSE. We also identified a unique profile of VTE risk factors such as major surgery (52.6%) in surgical patients and acute infection and/or rheumatologic disorder (42.2%) in medical patients. Overall, 58.9% of patients had > 2 VTE risk factors. In contrast, the ENDORSE study reported chronic pulmonary disease, chronic heart failure, and obesity at the time of hospitalization, and immobilization during hospitalization, to be the most frequent risk factors in both medical and surgical patients. These differences may have occurred largely due to variations in profiles and races. Moreover, ENDORSE evaluated inpatients from a particular ward/floor only on a single day, which might have precluded accurate estimation of VTE risk factors. Interestingly, despite the distinct eligible populations, the RAMP study,16 in concordance with our findings, reported that 57.3% of Chinese ICU/ CCU patients had $ 2 VTE risk factors. 11
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615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659
Any prophylaxis administration (19.0% vs 9.3%) was probably higher in surgical patients than in medical
[
614
660
]
661
TABLE 5
] Proportion of Hospitalized Patients With Any VTE Risk Receiving Different Types of VTE Prophylaxis
662 663 664 665 666
Any Prophylaxis, No./Na (%; 95% CI)
VTE Risk Surgical and medical patients Surgical patients
Q15
717
Appropriate Prophylactic Method, No./Nb (%; 95% CI)
1,942/13,609 (14.3; 13.7-14.9)
971/9,411 (10.3; 9.7-10.9)
1,326/6,986 (19.0; 18.1-19.9)
825/6,986 (11.8; 11.0-12.6)
.
.
716 718 719 720 721
667
Very low
668
Low
44/971 (4.5; 3.2-5.9)
18/971 (1.9; 1.0-2.8)
723
669
Moderate
298/2,285 (13.0; 11.6-14.4)
199/2,285 (8.7; 7.5-9.9)
724
670
High
984/3,730 (26.4; 25.0-27.8)
608/3,730 (16.3; 15.1-17.5)
725 726
671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715
Medical patients
616/6,623 (9.3; 8.65-10.0)
146/2,425 (6.0; 5.1-7.0)
Low
304/4,198 (7.2; 6.4-8.0)
.
High
312/2,425 (12.9; 11.5-14.2)
146/2,425 (6.0; 5.1-7.0)
722
727 728 729
No. ¼ number of patients who received the prophylaxis; Na ¼ number of patients who had any VTE risk; Nb ¼ number of patients who needed to receive appropriate prophylaxis as per the CHEST guidelines, 9th edition (among surgical patients, all other patients except those at a very low risk needed to receive prophylaxis; among medical patients, only high-risk patients needed to receive prophylaxis).
patients because research has shown a higher risk of VTE in patients undergoing surgery.21 Furthermore, any type of prophylaxis was administered to orthopedic surgery patients the most (66.4%), probably because they have the highest risk of VTE,22 and orthopedists are highly aware of VTE prevention. At-risk patients in ENDORSE received nearly five times more CHEST-recommended prophylaxis than those in DissolVE-2 (50.2% vs 10.3%). Furthermore, the implementation of appropriate prophylaxis (3.6%) was far lower than previous observations.23,24 In Canada, approximately 16% of acutely ill patients received appropriate prophylaxis,25 whereas in the Venous Thromboembolism Prophylaxis in Intensive Care Unit Patients (VOICE) study, 31.2% of patients received pharmacologic treatment and 44.2% received a combination of pharmacologic and mechanical prophylaxis.22 The disparity in CHEST-recommended prophylaxis between DissolVE-2 and other studies could have occurred because we stringently defined “CHESTrecommended prophylaxis,” after considering key elements in a prophylaxis course such as initiation time, modalities, and duration. 11
Only 14.3% of at-risk patients received some form of prophylaxis, with approximately 10.3% receiving the “correct’’ prophylactic method. The trend of appropriate prophylaxis being administered to at-risk patients was observed even after geographical stratification, suggesting physicians across China are like-minded. These implementation rates suggest that physicians are aware of VTE risks but often do not comply with guideline recommendations, probably due to lack of medical education and enforcement or due to genuine concerns regarding the relevance of foreign guidelines to Chinese patients.
Estimating the distribution of VTE events during hospitalization was our exploratory objective. The incidence of in-hospital VTE reported in the present study (0.3%) is higher than values reported in the United Kingdom (0.21% in 2010 to 0.14% in 2016)26 but similar to that of the United States (0.3%).27 These findings imply that the current VTE prevention strategies are far less than optimal and also have some crucial implications for health-care resource planning. The results of DissolVE-2 may be of significance from several perspectives. The gap between recommended and administered VTE prophylaxis can garner attention from both practitioners and hospital management, leading to enhanced medical education regarding inhospital VTE prophylaxis and interventions to make VTE risk-assessment systems at the ward or hospital level mandatory. Chinese local academic associations can also consider and revise their guidelines or consensus based on the current data. From the national health-care perspective, DissolVE-2 will contribute significant insights to the decision-making capabilities of the current health-care system in China, as well as reinforce action regarding resource planning because it can be an important reference to prospectively study the burden of thrombosis and bleeding risk associated with prophylaxis or its absence. There are a few limitations in our study. DissolVE-2 was conducted retrospectively and hence was unable to determine causal inferences between VTE risk level and obtaining appropriate prophylaxis. Moreover, patient chart data instead of interview data were used, which could have caused some inaccuracies in obtaining the latest information. The hospitals chosen for this study
7
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730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770
771
represented the best care available in China and thus might not depict the general level of care given. Considering China’s population density, there was a positive skew toward the inclusion of hospitals from South and East China compared with the Northwestern region. Moreover, patient data from several provinces were lacking, which if added, might potentially change the results. Bleeding risk factors were analyzed for the whole cohort and not after stratifying the patients on the basis of VTE risk. Hence, we cannot interpret the risk factors based on the risk level.
772 773 774 775 776 777 778 779 780 781 782
826
Conclusions The DissolVE-2 study provided a nationwide perspective on the real-world clinical practice of VTE risk assessment and prophylaxis implementation in China. It showed that although a considerable proportion of medical and surgical patients are at risk of VTE, implementation of VTE prophylaxis is low, especially in medical patients. Furthermore, these findings highlight the need for greater awareness and actions from both physicians and the government to tackle the growing burden of VTE.
783
827 828 829 830 831 832 833 834 835 836 837 838
784
839
785
840
Acknowledgments
786
Q9
Author contributions: C. W. is the guarantor of the article and takes responsibility for the content of the manuscript, including integrity of the data and accuracy of the analysis. Z. G. Z. and C. W. conceptualized and designed the study. Z. G. Z., X. Y. Q., Y. K. S., R. H. X., W. M. L., Q. C. K., J. M. Q., Z. Z., and C. W. participated in data acquisition; Z. G. Z., Z. Z., and C. W. analyzed and interpreted the data; and Z. G. Z., Z. Z., and C. W. drafted the manuscript. All authors provided final approval of the version to be published.
Q10
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: All the authors declare support from Sanofi for the submitted work. C. W., Z. G. Z., X. Y. Q., Y. K. S., R. H. X., W. M. L., Q. C. K., Y. M. X., and J. M. Q. were members of the DissolVE steering committee. Z. G. Z., X. Y. Q., Y. K. S., R. H. X., W. M. L., Q. C. K., J. M. Q., Y. M. X., and C. W. have received consultancy fees and clinical research funding from Sanofi. None declared: (Z. Z.).
787 788 789 790
Q13
791 792 793 794 795 796 797 798 799 800 801 802 803 804 805
Q11
Role of the sponsors: This study was funded by Sanofi, and editorial support in the preparation of this publication was provided by Sanofi. The authors individually and collectively are responsible for all content and editorial decisions and received no payment from Sanofi related to the development/ presentation of this publication.
Q12
Other contributions: The authors thank Bruce Davidson and Alexander T. Cohen for their valuable suggestions on the design of the study and revision of the manuscript. They also thank Leo J. Philip Tharappel and Amit Bhat (Indegene Pvt Ltd) for providing editorial support for the development of the manuscript.
806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825
Data sharing: Qualified researchers may request access to patient-level data and related study documents, including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient-level data will be anonymized and study documents will be redacted to protect the privacy of our trial participants. Further details on Sanofi’s data-
8 Original Research
sharing criteria, eligible studies, and process for requesting access can be found at: https:// www.clinicalstudydatarequest.com/. Additional information: The e-Tables can be found in the Supplemental Materials section of the online article.
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