Time-to-event analyses of lower-limb venous thromboembolism in aged patients undergoing lumbar spine surgery: a retrospective study of 1620 patients

Introduction

It is well-known that venous thromboembolism (VTE) is a major postoperative complication and a common and potentially lethal disease; VTE includes pulmonary embolism (PE) and deep venous thrombosis (DVT) [1–10]. VTE may cause severe morbidity, lead to poor life quality, and even death because of PE. It is estimated that around 50% of untreated DVT events can be complicated by PE; likewise, if untreated, 50% to 80% of PE cases are related to DVT events [5, 11]. Previous studies have uncovered that VTE events are possibly associated with the following risk factors: D-dimer, trauma, smoking, obesity, advanced age, neurological deficit, immobilization, malignancy, blood transfusion, major surgery, hospitalization, and inherited hypercoagulable state [12–16].

The risk for a VTE event increases after patients undergo surgical operations, such as a spinal operation [17, 18]. Annually, worldwide spinal operations are on the rise [19, 20]. Hence, it is important to seek proper management to reduce possible VTE events among patients who undergo spinal operations. In terms of patients undergoing spinal surgeries, the risks of VTE formation probably include a loss of muscular tension, postoperative bed rest, long-time horizontal abdominal position, and vascular compression by intraoperative retractors. It has been well documented in our previous study that around 15% of patients who undergo spinal operations—those without appropriate prophylaxis—progress to experiencing DVT events [21]. Particularly, a VTE event is considered to be highly associated with advanced age; accordingly, in previous studies, advanced age has been identified as an important risk contributing to VTE events after spine surgeries [5, 6, 22, 23].

Although the various risk factors of VTE events after spinal surgeries have been reported in previous studies [7, 24], understanding these findings is still elusive because of the selection of patient samples; this is likely to create more difficulties in understanding VTE development after spine surgery. Furthermore, the time to VTE events for aged patients after undergoing spinal operations has yet to be well elucidated. Therefore, the current study aims to uncover the occurrence and timing of VTE events after spinal operations by only recruiting an aged population (age≥60 yr).

Results

Time-to-event analysis of VTE

In the current study, all included patients had undergone lower extremity ultrasonography pre- and postoperatively at the first, second, fourth, eighth, and twelfth weeks. Thus, time-to-event Kaplan-Meier survival analyses were carried out to determine the potential risks causing postoperative VTE. As shown in Figure 1, an overall survival curve indicates that most VTE events occurred in the first week after spine surgery, followed by the second week (P<0.001), which was further supported by a cumulative hazard model.

Figure 1. Overall Kaplan-Meier analysis. (A) Time-to-event analysis of postoperative VTE incidences; (B) Cumulative hazard model (log-rank test, P<0.001).

Cox regression analysis

As shown in Table 3, a Cox regression analysis was carried out to further locate the risks of postoperative VTE. Consequently, advanced age (OR=1.108; 95% CI, 1.091–1.126), VTE history (OR=4.962; 95% CI, 3.849–6.397), and hypertension (OR=1.344; 95% CI, 1.084–1.667) were identified as the risk factors of postoperative VTE formation (all P<0.05). As shown in Figure 2, the cumulative survival curve indicated that most VTE events occurred in the first week after spine surgery (P<0.001), which was further confirmed by a cumulative hazard model (P<0.001). Furthermore, time-to-event Kaplan-Meier survival analyses were performed to determine the influence on postoperative VTE regarding VTE history and hypertension. Clearly, both VTE history and hypertension increased the risk of postoperative VTE formation, which is shown, respectively, in Figures 3, 4 (log-rank tests, both P<0.001). It revealed that the hazard growth mostly occurred in the first week after spine surgery, regardless of VTE history and hypertension (log-rank tests, both P<0.001).

Table 3. Cox regression analysis of postoperative VTE.

NO.	Items	B	p-value	Exp(B)	95% CI for Exp(B)
X1	Sex	0.043	0.709	1.044	(0.832, 1.311)
X2	Age	0.103	<0.001	1.108	(1.091, 1.126)
X3	Region	-0.019	0.862	0.981	(0.787, 1.221)
X4	Hospital stay	0.010	0.343	1.010	(0.989, 1.032)
X5	VTE history	1.602	<0.001	4.962	(3.849, 6.397)
X6	Hypertension	0.296	0.007	1.344	(1.084, 1.667)
X7	Diabetes	0.163	0.337	1.177	(0.844, 1.642)
X8	Heart disease	-0.337	0.190	0.731	(0.431, 1.182)
X9	Fusion	-0.313	0.166	0.731	(0.470, 1.139)
X10	Levels of fusion	0.102	0.232	1.107	(0.937, 1.309)
X11	Surgical duration	-0.001	0.311	0.999	(0.996, 1.001)
X12	Blood loss	<0.001	0.514	1.000	(0.999, 1.000)
X13	Blood transfusion	<0.001	0.237	1.000	(1.000, 1.001)
X14	Incision length	0.002	0.871	1.002	(0.981, 1.023)
X15	PTA	0.006	0.123	1.006	(0.998, 1.013)
X16	FIB	<0.001	0.997	1.000	(0.843, 1.186)
X17	TT	0.021	0.673	1.021	(0.927, 1.125)
X18	D-dimer	0.095	0.464	1.099	(0.853, 1.417)
X19	HDL	0.113	0.148	1.119	(0.961, 1.305)
X20	LDL	0.082	0.352	1.086	(0.913, 1.290)
X21	TC	0.007	0.933	1.007	(0.862, 1.176)
X22	TBIL	-0.002	0.955	0.998	(0.926, 1.075)
X23	DBIL	0.042	0.470	1.043	(0.930, 1.169)
X24	IBIL	-0.004	0.921	0.996	(0.924, 1.074)
X25	BMI	0.004	0.826	1.004	(0.972, 1.037)
VTE, venous thromboembolism; CI, confidence interval; PTA, prothrombin time activity; FIB, fibrinogen; TT, thrombin time; HDL, high density lipoprotein; LDL, low density lipoprotein; TC, total cholesterol; T-BIL, total bilirubin; D-BIL, direct bilirubin; I-BIL, indirect bilirubin; BMI, body mass index.

Figure 2. Cox regression multivariable analysis. (A) Time-to-event analysis of postoperative VTE incidences; (B) Cumulative hazard model (P<0.001).

Figure 3. Kaplan-Meier analysis regarding VTE history. (A) Time-to-event analysis of postoperative VTE incidences related to VTE history; (B) Cumulative hazard model (log-rank test, P<0.001).

Figure 4. Kaplan-Meier analysis regarding hypertension. (A) Time-to-event analysis of postoperative VTE incidence related to hypertension; (B) Cumulative hazard model (log-rank test, P<0.001).

Discussion

To the best of our knowledge, VTE is not uncommon in aged patients after lumbar spine surgery, regardless of fusion surgery; VTE events are reported to be highly correlated with the aging population [23]. However, the time-to-event analysis in aged patients has not been well documented. In our hospital, according to follow-up procedures, all patients who have undergone posterior spinal surgeries (regardless of fusion) are routinely requested to return for lower extremity ultrasonography pre- and postoperatively at the first, second, fourth, eighth, and twelfth weeks during their treatment. The current study focused on the time-to-event risk factors of postoperative VTE by utilizing medical records of aged 60 and over patients. Overall, a total of 1,620 cases were identified and recruited for the data analyses. Thus, the sample size is large enough to generate reliable results. As a result, 382 (23.6%) VTE events were found. All VTE events were asymptomatic, and most were calf DVT events (N=356). Univariable analyses did not indicate any statistical significances between the VTE group and non-VTE group in terms of gender proportion, regional distribution, diabetes, and heart disease.

Other studies have investigated VTE incidence after spine surgeries and reported a variety of data [7, 25–28]. Agarwal et al. [25] reported that only 0.6% of patients were documented with VTE events, including 28 DVT and 42 PE. This might be because the authors did not generate the results based on regular follow-ups using ultrasonography as we have done in the current study. Recently, Inoue et al. [26] performed an investigation of VTE events using indirect multidetector computed tomography in a prospective study including 105 cases that underwent spinal surgeries; they found that all VTE events were asymptomatic. The preoperative incidence of asymptomatic VTE was 4.8%, and the postoperative was 13.0%; the incidence of asymptomatic PE was 2.9% preoperatively and 8.0% postoperatively; and the incidence of asymptomatic DVT was 3.8% preoperatively and 6.0% postoperatively. The age, gender, BMI, surgical duration, blood loss, and specific comorbidities, including heart disease, hypertension, diabetes, previous VTE, and previous anticoagulant intake, were excluded from the risk factors. To a certain extent, the results in our study are in line with the reports above. Associated with postoperative VTE, our univariate analyses indicated that the duration of surgery, blood loss, and transfusion and the length of an incision between the VTE group and non-VTE group turned out to be statistically insignificant (all P>0.05). However, our work identified that advanced age, hypertension, VTE history, and prolonged hospital stay were risk factors for VTE formation. Compared with the non-VTE group, more patients in the VTE group had a previous VTE history and suffered from concurrent hypertension, but fewer patients in the VTE group underwent fusion surgery, which was more likely to be a protective factor. What may be the cause of such differences? As we can see, the reading of these findings is still somewhat questionable because of the selection of patient samples; this is likely to make the understanding of VTE progression after spine surgery less clear.

In the current study, time-to-event Kaplan-Meier survival analyses were conducted to determine the potential risks of postoperative VTE events. Consequently, an overall survival curve indicated that most VTE events occurred in the first week after spine surgery, followed by the second week; this was further supported by a cumulative hazard model. In addition, Cox regression analyses were carried out for further identification of the potential risk factors of postoperative VTE. Consequently, advanced age (OR=1.108; 95% CI, 1.091–1.126), VTE history (OR=4.962; 95% CI, 3.849–6.397), and hypertension (OR=1.344; 95% CI, 1.084–1.667) were identified as the risk factors for postoperative VTE formation. Furthermore, time-to-event Kaplan-Meier survival analyses were performed to determine the influence on postoperative VTE regarding VTE history and hypertension. Clearly, both VTE history and hypertension increased the hazard of postoperative VTE formation. It revealed that the highest hazard incidences mostly occurred in the first week after spine surgery, regardless of VTE history and hypertension. Previously, McClendon et al. [27] performed a retrospective time-to-event analysis for VTE progression after spinal fusion ≥ five levels. Likewise, they also identified VTE history as an independent risk factor for VTE formation. Cloney et al. [8] reported that the cumulative incidence of VTEs rose linearly in the first two postoperative weeks and then plateaued. By contrast, our findings show that the likelihood of VTE formation is the highest in the first postoperative week, followed by the second postoperative week. The differences in these results may be because of the different participants included in the studies, with only aged patients being recruited in our study.

Taken together, the current study has detected some significant correlations that can help in better understanding VTE progression in aged patients who undergo spinal operations. In addition, the risk factors identified in the current study can be regarded as early alerts for postoperative VTE events. Indeed, our study suggests that an early mechanical and/or chemoprophylaxis should be applied to aged patients as soon as possible, particularly during the first week after spine surgery. As a guidance here, it would be helpful to reduce postoperative VTE incidence in vulnerable, aged patients. However, the retrospective nature of the current study is bound to induce some limitations; the most obvious one is the study’s dependence on the quality of the data documented in the participants’ medical records. In fact, as the largest spinal medical center in our region, the present study might have incorporated some patients suffering from more severe diseases. As such, a future study should be designed as a prospective, multicenter, randomized controlled trial with a large sample size; this future study should be able to reveal stronger evidence and identify more possible risk factors that contribute to VTE events after spine surgery in aged patients.

Conclusions

In summary, the current study has identified that advanced age, VTE history, and hypertension are risk factors for postoperative VTE formation in aged patients, and VTE events are likely to occur mainly in the first postoperative week. Therefore, early mechanical and/or chemoprophylaxis should be applied to aged patients as soon as possible, particularly during the first week after spine surgery. As a guidance, it would be helpful to reduce postoperative VTE incidence in vulnerable, aged patients.

Patients and methods