Identification of prophylaxis and treatment for hospitalized patients associated with venous thromboembolism.

Abstract

To the Editor: Venous thromboembolism (VTE) is a collective term consisting of deep venous thrombosis (DVT) and pulmonary embolism (PE). It is a major worldwide health concern as it affects 5% to 15% of hospitalized patients. Various predisposing factors for VTE occurrence include cancer, surgery, prolonged immobilization, fracture, paralysis, oral contraceptive use, and hereditary coagulopathies. Since these risk factors and the occurrence of VTE in hospitalized patients depend on the cause of hospitalization, the American College of Chest Physicians (ACCP) guidelines (9th edition) recommend different scoring scales for VTE assessments. Despite the awareness of VTE prophylaxis becoming increasingly stronger, the burden of VTE is high, which suggests a prevalence of insufficient and substandard prophylaxes. The ACCP treatment guidelines recommend an appropriate anticoagulant-based treatment regimen for at least 3 months to reduce the risk of early recurrence and death. Furthermore, in recent years, the incidence of VTE has been increasing in China, suggesting that despite the ACCP guideline's recommendation, prophylaxis is not aggressively followed in China. Hence, we designed the current study to identify the proportion of patients who received appropriate VTE prophylaxes (those fully compliant with the ACCP guidelines, 9th edition), to determine the risk factors in previously hospitalized patients diagnosed with VTE, and to analyze the treatment pattern concerning its clinical outcomes in Chinese patients with VTE. We conducted a national, multicenter, non-interventional, observational registry study from January 2016 to December 2017, where patients’ hospitalization data were retrospectively collected within 6 weeks before VTE diagnosis and included a 3-month prospective follow-up period [Supplementary Figure 1, https://links.lww.com/CM9/B148]. Patients with a confirmatory diagnosis for VTE were recruited consecutively from 46 hospitals in China. The study was conducted in accordance with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) including all subsequent amendments. Institutional Ethical Committee approval was obtained from all the study centers (No. S2015-094-01). The risk stratification of VTE was assessed by the Padua prediction scoring (PPS) model for medical patients and the Caprini risk assessment (CRA) model for surgical patients. A detailed methodology is provided in the Supplementary Materials, https://links.lww.com/CM9/B148. Among the 1203 screened patients, a total of 1137 patients (50.7% of medical and 49.3% of surgical patients) who were confirmed with VTE were included in this analysis. Of them, 768 (67.6%) patients were diagnosed with DVT, 215 (18.9%) with PE, and 154 (13.5%) experienced both PE and DVT. More than half of the surgical patients were female (n = 332, 59.3%), while the medical patients were mostly males (n = 311, 53.9%). Compared with the medical patients, the surgical patients were younger (aged 58.0 vs. 65.0 years) with a slightly higher body mass index (24.2 vs. 23.9 kg/m2), and had a longer hospital stay (18 days vs. 15.5 days; Supplementary Table 1, https://links.lww.com/CM9/B148). The PPS model assessed 46.3% (95% confidence interval [CI], 42.1%–50.4%) of the medical patients were exposed to high risk of VTE, whereas 53.7% (95% CI, 49.6%–57.9%) of the surgical patients were at low risk. Surgical patients had a higher proportion of high-risk VTE as evaluated by the CRA model (77.0%; 95% CI, 73.3–80.4%). The proportions of low and moderate risk patients among surgical patients were 2.7% (95% CI, 1.5–4.4%) and 20.4% (95% CI, 17.1–23.9%), respectively [Supplementary Table 2, https://links.lww.com/CM9/B148]. The proportion of hospitalized patients at risk of VTE in our study was in mid-range as compared with the findings of the ENDORSE study (61.7% vs. 36.0%–73.0%) and surgical patients were at a higher risk of developing VTE as compared with medical.[1] Reduced physical activity (50.6%), age ≥70 years (41.2%), and active tumor (21.5%) were the most frequent risk factors for medical patients. In surgical patients, the major VTE risk factors were being bedridden for >72 h (64.5%), having undergone large open surgery (53.4%), and aged 41 to 60 years (40.7%; Supplementary Table 3, https://links.lww.com/CM9/B148). In this regard, Lutsey et al[2] reported that moderate- to high-intensity physical exercise reduced the risk of VTE compared with the low level of physical activity. In addition, in studies conducted by Gibbs[3] and Flordal,[4] long-term bed rest was associated with moderate risk for VTE. This suggests that VTE prophylaxis is indispensable. Among the overall 827 patients who were recommended for VTE prophylaxis according to the ACCP-9 guidelines, only 60 patients (7.3%; 95% CI, 5.6%–9.2%) received appropriate prophylaxis. A total of 349 patients (30.7%; 95% CI, 28.4%–34.0%) received any VTE prophylaxis, although not complying with the ACCP guidelines. Of the 267 medical patients at high risk, as assessed by the PPS model, 14 (5.2%; 95% CI, 2.9%–8.6%) patients were treated with appropriate prophylaxis. Of the 114 surgical patients at moderate risk and 431 surgical patients at high risk as assessed by CRA model, 46 (8.2%; 95% CI: 6.1%–10.8%) patients had received appropriate prophylaxis. Among the surgical patients, 7% (95% CI: 3.1%–13.4%) of patients at moderate risk and 8.8% (95% CI: 6.3%–11.9%) of patients at high risk received guideline-recommended VTE prophylaxis [Table 1]. These findings reveal that there is an extreme underutilization of VTE prophylaxis as compared with higher usage globally (7.3% vs. 49.5%).[1] This may result in an increase in the number of patients hospitalized due to VTE and related complications, increasing the clinical and economic burden. The ENDORSE study revealed that a higher proportion of at-risk medical patients received appropriate thromboprophylaxis in Western countries, including Germany (70%), Spain (64%), and Colombia (64%), disclosing a large gap between Western consensus guidelines and real-world clinical practice in China.[1] The low prevalence of appropriate VTE prophylaxis in China was also reported previously by a large multicenter study by Zhai et al,[5] which is in accordance with our findings. Fear of bleeding events is one of the main reasons for its suboptimal use in China. Other plausible reasons are the lack of awareness, and genuine concerns among physicians regarding the relevance of foreign VTE guidelines to Chinese patients. In the current study, the rate of appropriate prophylaxis was better in surgical patients than in medical patients. A probable reason for this could be the availability of specific guidelines for individual specialties, such as the availability of Chinese orthopedic guidelines. On the other hand, in the case of medical patients, the importance of appropriate VTE prophylaxis has gained significance only recently and there is an unmet need to increase the awareness among Chinese physicians. Alarmingly, we further found that only 3% of patients with malignant tumors received appropriate thromboprohylaxis [Supplementary Table 4, https://links.lww.com/CM9/B148]. None of the surgical patients with malignant tumors (0 of 117) were administered with VTE prophylaxis. This could be due to the perceived risk of bleeding in patients with a malignant tumor. Lukaszul et al, also found that there is insufficient usage of thromboprophylaxis in patients with cancer with VTE undergoing chemotherapy in Poland.[6] As VTE is the second main cause for mortality in patients with cancer, appropriate management to balance VTE and bleeding is a major therapeutic challenge worldwide. Hence, there is an urgent need for training the Chinese physicians to establish standard VTE prophylaxis based on the risk assessment in these patients. Table 1 - Proportion of receiving VTE prophylaxis according to the risk of VTE. Items n/N (%) 95% CI Appropriate prophylaxis 60/827 (7.3) (5.6%, 9.2%) Medical patients∗ 14/267 (5.2) (2.9%, 8.6%) High risk 14/267 (5.2) (2.9%, 8.6%) Surgical patients 46/560 (8.2) (6.1%, 10.8%) Low risk 0/15 (0.0) (–, –) Moderate risk 8/114 (7.0) (3.1%, 13.4%) High risk 38/431 (8.8) (6.3%, 11.9%) Any prophylaxis 349/1137 (30.7) (28.0%, 33.5%) Medical patients 142/577 (24.6) (21.1%, 28.3%) Low risk 88/310 (28.4) (23.4%, 33.8%) High risk 54/267 (20.2) (15.6%, 25.5%) Surgical patients 207/560 (37.0) (33.0%, 41.1%) Low risk 3/15 (20.0) (4.3%, 48.1%) Moderate risk 33/114 (28.9) (20.8%, 38.2%) High risk 171/431 (39.7) (35.0%, 44.5%) ∗According to the ACCP guideline, prophylaxis was not recommended for medical patients with low risk. Therefore, 310 medical patients with low risk were excluded from the appropriate prophylaxis.ACCP: American College of Chest Physicians; CI: Confidence interval; VTE: Venous thromboemobolism; –: Not applicable. A total of 1066 (93.8%) patients received any treatment for VTE 3 months after VTE diagnosis. During follow-up period, 42.7% of patients finished therapy [Supplementary Table 5, https://links.lww.com/CM9/B148], while 3.3% completed the 3-month anticoagulant therapy as prescribed by doctors. Other patients ended treatment early, with a median anticoagulation time of 15 days (IQR: 8-42 days). Anticoagulation (93.2%) was the most common treatment measure for symptomatic VTE, followed by thrombolysis (19.1%) and interventional therapy (14.8%), while surgical thrombectomy (0.8%) was the least used treatment strategy [Supplementary Table 6, https://links.lww.com/CM9/B148]. Most commonly used anticoagulants were low-molecular-weight heparin (88.7%, of which enxoaparin sodium was most often prescribed [39.3%]), warfarin (43.5%), and rivaroxaban (28.9%; Supplementary Table 7, https://links.lww.com/CM9/B148). During the 3-month follow-up period, eight patients (0.7%) experienced a recurrence of VTE. None of them proceeded from DVT to PE. The median time from diagnosis of first VTE to recurrence was 43 days (IQR: 27–55 days). All of them received anticoagulant therapy, but none of them received appropriate treatment, including four patients administered with an incorrect pattern of anticoagulant therapy and another four patients receiving inadequate dosage, which was recommended by the ACCP guidelines, 9th edition. Seven out of these eight patients (87.5%) recurred during VTE treatment [Supplementary Table 8, https://links.lww.com/CM9/B148]. This is in agreement with findings from other studies in which anticoagulants were commonly prescribed (71.0% and 84.6%).[7] However, it is noteworthy to mention that more than one-third of patients stopped treatment early, and the median duration was 15 days, which is far below the standard therapy as recommended by the ACCP guidelines, 9th edition. This reflects poor patient compliance and lack of standard therapy. This highlights the importance of appropriate VTE treatment to reduce the early recurrence of VTE in patients. A total of 72 (6.3%) patients died during the follow-up period. Two patients died due to PE, and two deaths were associated with lethal bleeding due to anticoagulant therapy (where one received warfarin at 2.5 mg/day for 7 days and the other received enoxaparin sodium at 0.8 mL/12 h for 11 days, followed by warfarin at 4.3 mg/day for 54 days). Thirty-nine patients died due to other diseases such as cardiovascular illnesses and malignancy. Bleeding occurred in 28 patients during follow up, with an incidence of 2.5%, including clinically significant bleeding in six patients (21.4%) and minor bleeding in 22 patients (78.6%). Thus, the overall risk of VTE is high in hospitalized patients in China. However, the rate of implementation of ACCP–recommended prophylaxis and standardized treatment is very low. It is therefore pivotal for healthcare professionals to improve awareness of VTE, and establish appropriate prophylaxes based on the risk assessment. Further studies are required to substantiate the potential benefits of appropriate VTE prophylaxes in reducing the incidence in high-risk hospitalized patients and standard treatment in reducing early recurrence. Acknowledgments Medical writing support, under the direction of the authors, was provided by Dr. Amit Bhat, Ph.D. (Indegene Pvt. Ltd., Bangalore) and funded by Sanofi. Funding This study was sponsored and funded by Sanofi. Conflicts of interest 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. Dan Shen is a Sanofi employee and may hold shares and/or stock options in the company. The other authors declare that there is no conflict of interest.