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Muscular Calf Vein Thrombosis Is Associated With Increased 30-Day Mortality But Not 90-Day Mortality in Older Patients With Hip Fracture

Open AccessPublished:September 18, 2022DOI:https://doi.org/10.1016/j.amjcard.2022.08.018
      Calf deep vein thrombosis (DVT) is common in patients with hip fractures. However, studies on whether calf DVT has an impact on the prognosis are limited. This retrospective cohort study explored the association between calf DVT and 30-day and 90-day all-cause mortality in older patients with hip fractures. A total of 564 consecutive patients who underwent ultrasound examination were identified from our hip fracture database and categorized into patients with calf DVT (axial DVT, muscular DVT) and no DVT. Of these, 86 patients (15.2%) had ultrasound-confirmed calf DVT, including 66 patients with muscular DVT, and 20 patients with axial DVT. The 30-day and 90-day all-cause mortality were 2.5% and 6.0%, respectively. Multivariate Cox analysis showed that calf DVT was significantly associated with an increased risk of 30-day mortality (hazard ratio [HR] 3.21, 95% confidence interval [CI] 1.05 to 9.84, p = 0.04), but this risk relationship did not persist at 90-day follow-up (HR 1.59, 95% CI 0.69 to 3.71, p = 0.28). When calf DVT was further categorized, muscular DVT remained an independent risk factor for 30-day mortality (HR 3.95, 95% CI 1.18 to 13.15, p = 0.03), whereas this relationship was not found in axial DVT (HR 1.79, 95% CI 0.21 to 15.02, p = 0.59). In conclusion, calf DVT, especially muscular calf DVT but not axial DVT, is independently associated with an increased risk of 30-day mortality in older patients with hip fracture, but this risk relationship did not persist at 90-day follow-up.

      Introduction

      Venous thromboembolism (VTE), consisting of pulmonary embolism (PE) and deep vein thrombosis (DVT), is a major health issue affecting approximately 10 million people every year worldwide.
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      Although distal DVT (also known as calf DVT) patients are numerous and represent 30% to 50% of all extremity DVTs,
      • Kuczmik W
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      • White L
      • McBane 2nd, RD
      Calf vein thrombosis comparison of outcomes for axial and muscular venous thrombosis.
      ,
      • Vlazny DT
      • Pasha AK
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      • Bartlett M
      • Houghton D
      • Casanegra AI
      • Daniels P
      • Froehling DA
      • White LJ
      • Hodge DO
      • McBane 2nd, RD
      Outcome of anticoagulation in isolated distal deep vein thrombosis compared to proximal deep venous thrombosis.
      studies on whether the calf DVT has an impact on the prognosis are limited, and existing results remain controversial.
      • Nishiwaki S
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      • Tsuyuki Y
      • Saga S
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      • Togi K
      • Mabuchi H
      • Takabayashi K
      • Shiomi H
      • Kato T
      • Makiyama T
      • Ono K
      • Inoko M
      • Kimura T
      COMMAND VTE Registry Investigators. Impact of no, distal, and proximal deep vein thrombosis on clinical outcomes in patients with acute pulmonary embolism: From the COMMAND VTE registry.
      • Mahajan A
      • Brunson A
      • Eldredge J
      • White RH
      • Keegan THM
      • Wun T.
      Incidence and outcomes associated with 6,841 isolated distal deep vein thromboses in patients with 13 common cancers.
      • Galanaud JP
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      • Bosson JL
      • Laroche JP
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      • Brisot D
      • Boge G
      • van Kien AK
      • Gattolliat O
      • Bettarel-Binon C
      • Gris JC
      • Genty C
      • Quere I
      OPTIMEV-SFMV Investigators
      Comparative study on risk factors and early outcome of symptomatic distal versus proximal deep vein thrombosis: results from the OPTIMEV study.
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      Usually, isolated calf DVT is generally considered as benign,
      • Schellong S
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      • Chee KH
      • Schulman S
      • Singer DE
      • Desch M
      • Tang W
      • Voccia I
      • Zint K
      • Goldhaber SZ.
      Profile of patients with isolated distal deep vein thrombosis versus proximal deep vein thrombosis or pulmonary embolism: RE-COVERY DVT/PE Study.
      and the current guideline recommend serial ultrasound imaging for 2 weeks over anticoagulation therapy unless patients have severe symptoms or risk factors for thrombus extension.
      • Stevens SM
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      • Lake E
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      • Vintch JRE
      • Wells PS
      • Moores LK.
      Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report.
      With an aging population, the number of hip fractures is increasing and is strongly associated with substantial excess mortality.
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      ,
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      At the same time, the prevalence of DVT in hip fracture is also high, reaching 20.0% to 35.0%, typically occurring in the calf.
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      • Cong YX
      • Zhuang Y
      • Zhang K.
      Deep vein thrombosis in bilateral lower extremities after hip fracture: a retrospective study of 463 patients.
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      • Lv Y
      • Yang Z
      • Hou G.
      Clinical predictors for deep vein thrombosis on admission in patients with intertrochanteric fractures: a retrospective study.
      Using our own hip fracture database focusing on the prognosis,
      • Wang ZC
      • Jiang W
      • Chen X
      • Yang L
      • Wang H
      • Liu YH.
      Systemic immune-inflammation index independently predicts poor survival of older adults with hip fracture: a prospective cohort study.
      we first explored the association between calf DVT and mortality in these patients. Calf DVT involves either axial or muscular venous segments, and their clinical features and outcomes are quite different.
      • Kuczmik W
      • Wysokinski WE
      • Hesley GK
      • Vlazny DT
      • Houghton DE
      • Swanson KE
      • Casanegra AI
      • Hodge D
      • White L
      • McBane 2nd, RD
      Calf vein thrombosis comparison of outcomes for axial and muscular venous thrombosis.
      Therefore, we further investigated whether this relationship was affected by anatomic location (axial DVT, muscular DVT).

      Methods

      Consecutive older hip fracture patients between January 1, 2016, and November 1, 2021, were identified by reviewing our hip fracture database. This clinical database has previously been reported in detail.
      • Wang ZC
      • Jiang W
      • Chen X
      • Yang L
      • Wang H
      • Liu YH.
      Systemic immune-inflammation index independently predicts poor survival of older adults with hip fracture: a prospective cohort study.
      Patients were excluded from this study if they did not undergo ultrasound examination during hospitalization, or the thrombus involved the proximal veins of the lower extremity, or follow-up information was not available. The study flowchart is represented in Figure 1. All included patients underwent a color Doppler ultrasonography of both lower extremities by an experienced radiologist, and results were reconfirmed by another senior radiologist. According to thrombus location, calf DVT were then divided into either axial DVT group (anterior tibial vein, posterior tibial vein, fibular vein) or muscular DVT group (gastrocnemius vein, soleal vein). Patients with both axial and muscular vein thrombosis were placed in the axial DVT group. The study complies with the Declaration of Helsinki. The protocol was approved by the Institutional Ethics Committee of Deyang People's Hospital (Number: 2021-04-019-K01). As this study was a retrospective study of anonymous data, informed consent was waived by the committee.
      Figure 1
      Figure 1Flowchart of the study participants.
      As described previously,
      • Wang Z
      • Chen X
      • Wu J
      • Zhou Q
      • Liu H
      • Wu Y
      • Liu S
      • Liu Y.
      Low mean platelet volume is associated with deep vein thrombosis in older patients with hip fracture.
      data were extracted from our clinical database, including age at admission (years), gender (male/female), smoking status (yes/no), comorbidities (hypertension, diabetes mellitus, chronic respiratory disease, stroke, atrial fibrillation, renal disease, cancer, liver disease, connective tissue disease, varicose vein), hip fracture type (femur neck fracture/intertrochanteric fracture), anticoagulant therapy (yes/no) and anticoagulant drugs. Hip fracture patients in our institution received anticoagulant therapy according to the guideline recommendation.
      • Falck-Ytter Y
      • Francis CW
      • Johanson NA
      • Curley C
      • Dahl OE
      • Schulman S
      • Ortel TL
      • Pauker SG
      • Colwell Jr., CW
      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.
      Low-molecular-weight heparin (enoxaparin, 4,000 AxaIU/0.4 ml), or fondaparinux (2.5 mg) was administered subcutaneously once daily. Meanwhile, plantar arteriovenous pump (20 min, twice per day) was used to promote blood reflux.
      After discharge, all surviving patients were followed up at 30 and 90 days by telephone interviews. The follow-up items included survival status and time of death. If patients died in hospital, death information was obtained from medical record. Survival time was defined as the time from the data of ultrasound examination to death or last follow-up (January 31, 2022), whichever was earlier. The outcomes of interest were 30- and 90-day all-cause mortality. The time frame of 90 days was selected according to the previous studies evaluating short-term mortality for DVT.
      • Vlazny DT
      • Pasha AK
      • Kuczmik W
      • Wysokinski WE
      • Bartlett M
      • Houghton D
      • Casanegra AI
      • Daniels P
      • Froehling DA
      • White LJ
      • Hodge DO
      • McBane 2nd, RD
      Outcome of anticoagulation in isolated distal deep vein thrombosis compared to proximal deep venous thrombosis.
      ,
      • Nishiwaki S
      • Morita Y
      • Yamashita Y
      • Morimoto T
      • Amano H
      • Takase T
      • Hiramori S
      • Kim K
      • Oi M
      • Akao M
      • Kobayashi Y
      • Toyofuku M
      • Izumi T
      • Tada T
      • Chen PM
      • Murata K
      • Tsuyuki Y
      • Saga S
      • Sasa T
      • Sakamoto J
      • Kinoshita M
      • Togi K
      • Mabuchi H
      • Takabayashi K
      • Shiomi H
      • Kato T
      • Makiyama T
      • Ono K
      • Inoko M
      • Kimura T
      COMMAND VTE Registry Investigators. Impact of no, distal, and proximal deep vein thrombosis on clinical outcomes in patients with acute pulmonary embolism: From the COMMAND VTE registry.
      ,
      • Raskob GE
      • Spyropoulos AC
      • Cohen AT
      • Weitz JI
      • Ageno W
      • De Sanctis Y
      • Lu W
      • Xu J
      • Albanese J
      • Sugarmann C
      • Weber T
      • Lipardi C
      • Spiro TE
      • Barnathan ES.
      Association between asymptomatic proximal deep vein thrombosis and mortality in acutely ill medical patients.
      The normality of continuous variables was checked using the Shapiro-Wilk test, and presented as mean±SD or median (interquartile range [IQR]) based on their distributions. Differences between mean or median were compared using t test or Wilcoxon rank-sum test as appropriate. Categorical variables were described as numbers (%) and analyzed by chi-square test or Fisher's exact test. Survival analysis was also performed using Kaplan-Meier survival curves, and differences between groups were estimated using the log-rank test. Univariate Cox proportional hazard models were used to identify factors associated with all-cause mortality. Variables with p <0.10 in univariate Cox models ([calf/muscular/axial DVT], gender, hip fracture type, anticoagulant therapy) and statistically meaningful baseline data (age) were further included in the multivariate Cox regression analysis. The proportional hazard assumption was assessed using Schoenfeld residuals. Considering that cancer can affect the survival of DVT patients,
      • Mahajan A
      • Brunson A
      • Eldredge J
      • White RH
      • Keegan THM
      • Wun T.
      Incidence and outcomes associated with 6,841 isolated distal deep vein thromboses in patients with 13 common cancers.
      a subsequent sensitivity analysis was performed including only patients without cancer. All reported p values are 2-sided, and p < 0.05 was considered statistically significant. All analyses were conducted by the use of JMP Pro software (version 16.0.0; SAS Institute Inc., Cary, North Carolina).

      Results

      Of 564 patients included in the final study, 86 patients (15.2%) had ultrasound-confirmed calf DVT, whereas the remaining 478 patients (84.8%) had no DVT. Patient characteristics are summarized in Table 1. The mean age was 79.1 years, 65.8% were female, and the vast majority of patients (95.7%) received anticoagulation therapy. Compared with patients without DVT, patients with calf DVT were more likely to be older and have intertrochanteric fracture (p < 0.05). However, no significant differences were observed regarding gender, smoking, comorbidities, anticoagulant therapy and anticoagulant drugs. Among patients with calf DVT, 66 had muscular DVT (76.7%), and 20 had axial DVT (23.3%). As shown in Table 2, patient characteristics were similar between muscular DVT and axial DVT except for age (p < 0.05).
      Table 1Baseline characteristics of patients with calf DVT or without DVT
      VariableTotal (n = 564)Calf DVT (n = 86)No DVT (n = 478)p
      Age (years), mean ± SD79.1 ± 8.680.8 ± 7.078.7 ± 8.90.04
      Female, n (%)371 (65.8)61 (70.9)310 (64.9)0.27
      Smoking, n (%)102 (18.1)13 (15.1)89 (18.6)0.44
      Comorbidities, n (%)
       Hypertension254 (45.0)44 (51.2)210 (43.9)0.22
       Diabetes mellitus118 (20.9)22 (25.6)96 (20.1)0.25
       Chronic respiratory disease94 (16.7)14 (16.3)80 (16.7)0.92
       Stroke68 (12.1)12 (14.0)56 (11.7)0.56
       Atrial fibrillation45 (8.0)7 (8.1)38 (8.0)0.95
       Renal disease32 (5.7)3 (3.5)29 (6.1)0.34
       Cancer26 (4.6)2 (2.3)24 (5.0)0.27
       Liver disease11 (2.0)1 (1.2)10 (2.1)0.57
       Connective tissue disease9 (1.6)2 (2.3)7 (1.5)0.56
       Varicose vein7 (1.2)1 (1.2)6 (1.3)0.94
      Hip fracture type, n (%)0.01
       Femoral neck fracture263 (46.6)29 (33.7)234 (49.0)
       Intertrochanteric fracture301 (53.4)57 (66.3)244 (51.0)
       Anticoagulant therapy, n (%)540 (95.7)85 (98.8)455 (95.2)0.12
      Anticoagulant drugs, n (%)0.29
       Enoxaparin447 (82.8)67 (78.8)380 (83.5)
       Fondaparinux93 (17.2)18 (21.2)75 (16.5)
      DVT = deep vein thrombosis; SD = standard deviation.
      Table 2Baseline characteristics of patients with muscular or axial DVT
      VariableMuscular DVT (n = 66)Axial DVT (n = 20)p
      Age (years), mean ± SD79.8 ± 6.784.2 ± 6.90.01
      Female, n (%)49 (74.2)12 (60.0)0.22
      Smoking, n (%)8 (12.1)5 (25.0)0.16
      Comorbidities, n (%)
       Hypertension34 (51.5)10 (50.0)0.91
       Diabetes mellitus19 (28.8)3 (15.0)0.22
       Chronic respiratory disease11 (16.7)3 (15.0)0.86
       History of stroke10 (15.2)2 (10.0)0.56
       Atrial fibrillation4 (6.1)3 (15.0)0.20
       Renal disease3 (4.6)0 (0.0)1.00
       Cancer2 (3.0)0 (0.0)1.00
       Liver disease0 (0.0)1 (5.0)0.23
       Varicose vein1 (1.5)0 (0.0)1.00
      Connective tissue disease2 (3.0)0 (0.0)1.00
      Hip fracture type, n (%)0.14
       Femoral neck fracture25 (37.9)4 (20.0)
       Intertrochanteric fracture41 (62.1)16 (80.0)
       Anticoagulant therapy, n (%)65 (98.5)20 (100.0)0.58
      Anticoagulant drugs, n (%)0.27
       Enoxaparin53 (81.5)14 (70.0)
       Fondaparinux12 (18.5)6 (30.0)
      DVT = deep vein thrombosis; SD = standard deviation.
      After 30 day follow-up, 14 of 564 patients (2.5%) died from all causes. Compared with patients without DVT, patients with calf DVT suffered a higher 30-day mortality (5.8% vs 1.9%, p = 0.03). Also, Kaplan-Meier survival curve displayed significantly worse survival in patients with calf DVT at 30 day follow-up (Log-rank chi-square: 4.72, p = 0.03; Figure 2a). After adjusting for variables that demonstrated significance in univariate analyses, this relationship remained significant (HR 3.21, 95% CI 1.05 to 9.84, p = 0.04), and anticoagulation therapy was significantly associated with a reduced 30-day mortality (HR 0.16, 95% CI 0.03 to 0.75, p = 0.02, Table 3).
      Figure 2
      Figure 2Kaplan-Meier curves for 30-day all-cause mortality by DVT type. (a) calf DVT; (b) muscular DVT; (c) axial DVT.
      Table 3Univariate and multivariate Cox regression analysis for the risk factors associated with 30-day all-cause mortality
      VariableUnivariateMultivariate
      HR (95% CI)pHR (95% CI)p
      Calf DVT3.15 (1.06–9.40)0.043.21 (1.05–9.84)0.04
      Age1.05 (0.98–1.12)0.171.03 (0.97–1.11)0.37
      Male2.59 (0.90–7.47)0.082.82 (0.98–8.17)0.06
      Intertrochanteric fracture3.22 (0.90–11.54)0.073.28 (0.88–12.31)0.08
      Anticoagulant therapy0.25 (0.06–1.12)0.070.16 (0.03–0.75)0.02
      CI = confidence interval; DVT = deep venous thrombosis; HR = hazard ratio.
      When patients with calf DVT were further categorized based on thrombus location, patients with muscular DVT had poor survival compared with patients without DVT (Log-rank chi-square: 4.46, p = 0.04; Figure 2b), but patients with axial DVT lost statistical significance (Log-rank chi-square: 0.921, p = 0.34; Figure 2c). Multivariate Cox regression analysis also confirmed that muscular DVT remained an independent risk factor for 30-day mortality (HR 3.95, 95% CI 1.18 to 13.15, p = 0.03), whereas this relationship was not found in axial DVT (HR 1.79, 95% CI 0.21 to 15.02, p = 0.59, Table 4). Moreover, gender ([men], HR 2.98, 95% CI 1.02 to 8.71, p = 0.04) and anticoagulation therapy (HR 0.16, 95% CI 0.03 to 0.77, p = 0.02) were significantly associated with 30-day mortality.
      Table 4Univariate and multivariate Cox regression analysis for the risk factors associated with 30-day all-cause mortality
      VariableUnivariateMultivariate
      HR (95% CI)pHR (95% CI)p
      Muscular DVT3.31 (1.02–10.74)0.043.95 (1.18–13.15)0.03
      Axial DVT2.65 (0.34–20.93)0.361.79 (0.21–15.02)0.59
      Age1.05 (0.98–1.12)0.171.04 (0.97–1.12)0.30
      Male2.59 (0.90–7.47)0.082.98 (1.02–8.71)0.04
      Intertrochanteric fracture3.22 (0.90–11.54)0.073.43 (0.91–12.91)0.07
      Anticoagulant therapy0.25 (0.06–1.12)0.0690.16 (0.03–0.77)0.02
      CI = confidence interval; DVT = deep venous thrombosis; HR = hazard ratio.
      During follow-up of 90 days, 34 patients (6.0%) died. Patients with calf DVT had a higher 90-day mortality (8.1% vs 5.6%), but the difference did not reach statistical significance (p = 0.37). After adjusting for the same variables as the 30-day mortality analysis, calf DVT (HR 1.59, 95% CI 0.69 to 3.71, p = 0.28), muscular DVT (HR 1.63, 95% CI 0.62 to 4.27, p = 0.32), and axial DVT (HR 1.51, 95% CI 0.35 to 6.59, p = 0.58) were not associated with 90-day mortality.
      Considering that cancer can affect the survival of patients with DVT, we further performed a sensitivity analysis by excluding all patients with cancer from the main analysis. Consistent with the main findings, calf DVT (HR 3.19, 95% CI 1.05 to 9.71, p = 0.04) and muscular DVT (HR 3.82, 95% CI 1.15 to 12.68, p = 0.03) were significantly associated with 30-day mortality, whereas axial DVT did not show a correlation with survival outcome (HR 1.65, 95% CI 0.20 to 13.85, p = 0.65).

      Discussion

      Usually, isolated calf DVT is thought to be more benign than proximal DVT and PE.
      • Schellong S
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      Profile of patients with isolated distal deep vein thrombosis versus proximal deep vein thrombosis or pulmonary embolism: RE-COVERY DVT/PE Study.
      Compression versus Anticoagulant treatment and compression in symptomatic Calf Thrombosis diagnosed by UltraSound (CACTUS) was the largest and most recent randomized controlled trial with 23 centers from 3 countries for calf DVT analysis, and 259 patients with isolated calf DVT were randomly assigned to receive either subcutaneous nadroparin or placebo for 42 days. Even in the placebo group, the rates of calf DVT extension to proximal veins and symptomatic PE were fairly low at 90 days (5.4% and 0.8%, respectively). In addition, they found that nadroparin was not superior to placebo in low-risk outpatients with calf DVT and increased the risk of bleeding.
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      As such, current guidelines recommend serial ultrasound imaging over anticoagulation for isolated patients with calf DVT without severe symptoms or extension risk factors.
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      • Wells PS
      • Moores LK.
      Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report.
      When patients received anticoagulant therapy, a large observational cohort study (GARGIELD-VTE Registry) showed that calf DVT was significantly less likely to experience VTE recurrence (4.8 vs 6.5/100 person-years), and all-cause death than proximal DVT at 12 months (4.6 vs 8.0/100 person-years).
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      Another study also confirmed that patients with calf DVT were at a lower risk of VTE recurrence (7.9% vs 17.3%) and all-cause death than patients with proximal DVT (25.7% vs 33.5%) beyond the first 3 years after acute thrombotic event.
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      However, studies on whether the calf DVT has an impact on the prognosis than those without DVT are limited, and existing results remain controversial.
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      • Akao M
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      • Izumi T
      • Tada T
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      • Saga S
      • Sasa T
      • Sakamoto J
      • Kinoshita M
      • Togi K
      • Mabuchi H
      • Takabayashi K
      • Shiomi H
      • Kato T
      • Makiyama T
      • Ono K
      • Inoko M
      • Kimura T
      COMMAND VTE Registry Investigators. Impact of no, distal, and proximal deep vein thrombosis on clinical outcomes in patients with acute pulmonary embolism: From the COMMAND VTE registry.
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      • Brunson A
      • Eldredge J
      • White RH
      • Keegan THM
      • Wun T.
      Incidence and outcomes associated with 6,841 isolated distal deep vein thromboses in patients with 13 common cancers.
      • Galanaud JP
      • Sevestre-Pietri MA
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      • Gris JC
      • Genty C
      • Quere I
      OPTIMEV-SFMV Investigators
      Comparative study on risk factors and early outcome of symptomatic distal versus proximal deep vein thrombosis: results from the OPTIMEV study.
      • Vaitkus PT
      • Leizorovicz A
      • Cohen AT
      • Turpie AG
      • Olsson CG
      • Goldhaber SZ
      PREVENT Medical Thromboprophylaxis Study Group. Mortality rates and risk factors for asymptomatic deep vein thrombosis in medical patients.
      A largest epidemiologic study including 6,841 patients with cancer with calf DVT reported that calf DVT was associated with worse overall mortality among all cancer types compared with those without VTE at 2 years (HR 1.56 to 4.60).
      • Mahajan A
      • Brunson A
      • Eldredge J
      • White RH
      • Keegan THM
      • Wun T.
      Incidence and outcomes associated with 6,841 isolated distal deep vein thromboses in patients with 13 common cancers.
      Another national, multicenter, prospective study (OPTimisation de l'Interrogatoire pour la Maladie thromboEmbolique Veineuse, OPTIMEV) also found that calf DVT exhibited a higher mortality than those without DVT (4.4% vs 3.3%, odds ratio 2.0, 95% CI 2.1 to 3.5).
      • Galanaud JP
      • Sevestre-Pietri MA
      • Bosson JL
      • Laroche JP
      • Righini M
      • Brisot D
      • Boge G
      • van Kien AK
      • Gattolliat O
      • Bettarel-Binon C
      • Gris JC
      • Genty C
      • Quere I
      OPTIMEV-SFMV Investigators
      Comparative study on risk factors and early outcome of symptomatic distal versus proximal deep vein thrombosis: results from the OPTIMEV study.
      However, other studies have failed to observe any association between calf DVT and mortality.
      • Nishiwaki S
      • Morita Y
      • Yamashita Y
      • Morimoto T
      • Amano H
      • Takase T
      • Hiramori S
      • Kim K
      • Oi M
      • Akao M
      • Kobayashi Y
      • Toyofuku M
      • Izumi T
      • Tada T
      • Chen PM
      • Murata K
      • Tsuyuki Y
      • Saga S
      • Sasa T
      • Sakamoto J
      • Kinoshita M
      • Togi K
      • Mabuchi H
      • Takabayashi K
      • Shiomi H
      • Kato T
      • Makiyama T
      • Ono K
      • Inoko M
      • Kimura T
      COMMAND VTE Registry Investigators. Impact of no, distal, and proximal deep vein thrombosis on clinical outcomes in patients with acute pulmonary embolism: From the COMMAND VTE registry.
      ,
      • Vaitkus PT
      • Leizorovicz A
      • Cohen AT
      • Turpie AG
      • Olsson CG
      • Goldhaber SZ
      PREVENT Medical Thromboprophylaxis Study Group. Mortality rates and risk factors for asymptomatic deep vein thrombosis in medical patients.
      Due to a high risk of calf DVT and mortality in older patients with hip fracture, this study was able to explore the association between calf DVT and all-cause mortality and found that calf DVT was significantly associated with an increased risk of 30-day mortality, which was consistent with the studies mentioned previously.
      • Mahajan A
      • Brunson A
      • Eldredge J
      • White RH
      • Keegan THM
      • Wun T.
      Incidence and outcomes associated with 6,841 isolated distal deep vein thromboses in patients with 13 common cancers.
      ,
      • Galanaud JP
      • Sevestre-Pietri MA
      • Bosson JL
      • Laroche JP
      • Righini M
      • Brisot D
      • Boge G
      • van Kien AK
      • Gattolliat O
      • Bettarel-Binon C
      • Gris JC
      • Genty C
      • Quere I
      OPTIMEV-SFMV Investigators
      Comparative study on risk factors and early outcome of symptomatic distal versus proximal deep vein thrombosis: results from the OPTIMEV study.
      Recently, some studies showed that isolated patients with calf DVT had a high prevalence of PE (> 30%), which is known to be associated with poor prognosis.
      • Kuczmik W
      • Wysokinski WE
      • Hesley GK
      • Vlazny DT
      • Houghton DE
      • Swanson KE
      • Casanegra AI
      • Hodge D
      • White L
      • McBane 2nd, RD
      Calf vein thrombosis comparison of outcomes for axial and muscular venous thrombosis.
      ,
      • Vlazny DT
      • Pasha AK
      • Kuczmik W
      • Wysokinski WE
      • Bartlett M
      • Houghton D
      • Casanegra AI
      • Daniels P
      • Froehling DA
      • White LJ
      • Hodge DO
      • McBane 2nd, RD
      Outcome of anticoagulation in isolated distal deep vein thrombosis compared to proximal deep venous thrombosis.
      ,
      • Kim SM.
      Clinical presentation of isolated calf deep vein thrombosis in inpatients and prevalence of associated pulmonary embolism.
      This might be a possible reason for the high mortality in patients with calf DVT. Of note, patients with cancer may be distinguished from patients without cancer; therefore, we performed a sensitivity analysis by excluding all patients with cancer, and the result was consistent with our main findings.
      In this study, this risk relationship did not persist at 90-day follow-up. Other studies also found that the difference in 90-day mortality between calf DVT and no DVT was not significant, including COMMAND VTE Registry study (2.5% vs 1.4%, HR 1.73, 95% CI 0.25 to 33.74)
      • Nishiwaki S
      • Morita Y
      • Yamashita Y
      • Morimoto T
      • Amano H
      • Takase T
      • Hiramori S
      • Kim K
      • Oi M
      • Akao M
      • Kobayashi Y
      • Toyofuku M
      • Izumi T
      • Tada T
      • Chen PM
      • Murata K
      • Tsuyuki Y
      • Saga S
      • Sasa T
      • Sakamoto J
      • Kinoshita M
      • Togi K
      • Mabuchi H
      • Takabayashi K
      • Shiomi H
      • Kato T
      • Makiyama T
      • Ono K
      • Inoko M
      • Kimura T
      COMMAND VTE Registry Investigators. Impact of no, distal, and proximal deep vein thrombosis on clinical outcomes in patients with acute pulmonary embolism: From the COMMAND VTE registry.
      and PREVENT study (3.39% vs 1.92%, HR 1.36, 95% CI 0.41 to 4.45).
      • Vaitkus PT
      • Leizorovicz A
      • Cohen AT
      • Turpie AG
      • Olsson CG
      • Goldhaber SZ
      PREVENT Medical Thromboprophylaxis Study Group. Mortality rates and risk factors for asymptomatic deep vein thrombosis in medical patients.
      A reason for this result might be related to thrombosis resolution. Houghton et al
      • Houghton DE
      • Lekah A
      • Macedo TA
      • Hodge D
      • Saadiq RA
      • Little Y
      • Casanegra AI
      • McBane RD
      • Wysokinski WE.
      Resolution of acute lower extremity deep vein thrombosis with Rivaroxaban compared to warfarin.
      found that nearly 93.7% of patients with DVT achieved total or partial resolution of thrombosis at 90 day follow-up, and these vessels were recanalized. Another reason may be the lack of statistical effectiveness owing to the small sample size.
      Recently, patients with axial DVT were found to be more likely to experience VTE recurrence, DVT propagation, and PE than those with muscular DVT.
      • Kuczmik W
      • Wysokinski WE
      • Hesley GK
      • Vlazny DT
      • Houghton DE
      • Swanson KE
      • Casanegra AI
      • Hodge D
      • White L
      • McBane 2nd, RD
      Calf vein thrombosis comparison of outcomes for axial and muscular venous thrombosis.
      To our knowledge, this was the first study to explore the associations between all-cause mortality and either axial DVT or muscular DVT. In line with our findings form calf DVT analysis, muscular DVT remained an independent risk factor for 30-day mortality but lost its statistical significance at 90-day follow-up. Limited studies have revealed that mortality did not differ between muscular DVT and axial DVT at 90 days (3.8% vs 4.1%)
      • Galanaud JP
      • Sevestre MA
      • Genty C
      • Laroche JP
      • Zizka V
      • Quéré I
      • Bosson JL
      OPTIMEV SFMV investigators
      Comparison of the clinical history of symptomatic isolated muscular calf vein thrombosis versus deep calf vein thrombosis.
      and 2 years (17.2% vs 16.5%).
      • Kuczmik W
      • Wysokinski WE
      • Hesley GK
      • Vlazny DT
      • Houghton DE
      • Swanson KE
      • Casanegra AI
      • Hodge D
      • White L
      • McBane 2nd, RD
      Calf vein thrombosis comparison of outcomes for axial and muscular venous thrombosis.
      Unfortunately, in this study, axial DVT did not show a correlation with survival outcome. The reason might be related to the small sample size of axial DVT (n = 20), and only 1 death occurred in this group.
      Moreover, 95.7% of patients with hip fracture in this study received anticoagulant therapy, and we found that anticoagulation therapy was significantly associated with a reduced 30-day mortality. This finding has been confirmed by many previous studies.
      • Vlazny DT
      • Pasha AK
      • Kuczmik W
      • Wysokinski WE
      • Bartlett M
      • Houghton D
      • Casanegra AI
      • Daniels P
      • Froehling DA
      • White LJ
      • Hodge DO
      • McBane 2nd, RD
      Outcome of anticoagulation in isolated distal deep vein thrombosis compared to proximal deep venous thrombosis.
      ,
      • Kuczmik W
      • Wysokinski WE
      • Macedo T
      • Froehling D
      • Daniels P
      • Casanegra A
      • Houghton D
      • Vlazny D
      • Meverden R
      • Lang T
      • White L
      • Hodge D
      • McBane RD.
      Calf vein thrombosis outcomes comparing anticoagulation and serial ultrasound imaging management strategies.
      A recent systematic review of randomized controlled trials has also revealed that anticoagulation therapy reduced the risk of VTE recurrence (risk ratio [RR] 0.34, 95% CI 0.15 to 0.77) and DVT recurrence (RR 0.25, 95% CI 0.10 to 0.67) and did not increase major bleeding (RR 0.76, 95% CI 0.13 to 4.62) compared with no intervention or placebo.
      • Kirkilesis G
      • Kakkos SK
      • Bicknell C
      • Salim S
      • Kakavia K.
      Treatment of distal deep vein thrombosis.
      However, several limitations need to be mentioned. First, although the overall sample size was relatively large, the sample sizes for calf DVT and death were very small, resulting in wide CIs and low statistical power. For this reason, the generalization of the current findings should be made with caution. Second, this was a retrospective study, some important variables related to death could not be accessed, such as anticoagulant duration, thrombus propagation, and bleeding. Third, all patients were identified from our institutional database, hence selection bias inevitably existed. To overcome these limitations, more prospective studies with large sample sizes are needed to validate our findings.
      In conclusion, calf DVT, especially muscular DVT but not axial DVT, is independently associated with an increased risk of 30-day mortality in older patients with hip fracture, but this risk relationship did not persist at 90-day follow-up. Therefore, calf DVT should receive more attention from clinicians, especially in the initial 30 days following an acute thrombotic event.

      Acknowledgment

      We would like to thank several nurses from the Department of Orthopedics in Deyang People's Hospital for the help with the data inspection.

      Authors’ Contributions

      Xi Chen: methodology, Formal analysis, Software, Visualization, Writing-original draft. Zhicong Wang: conceptualization, Writing-review and editing, Supervision, Validation, Funding acquisition. Hailong Liu: methodology, Formal analysis, Writing-review and editing, Project administration. Jianjun Zhang: investigation, Supervision, validation. Zhonglun Zhu: investigation, Supervision, validation. Yan Chen: investigation, Supervision, validation. Mozhen Liu: investigation, Supervision, validation. Qing Zhou: conceptualization, Writing-review & editing, Supervision, Validation.

      Disclosures

      The authors have no competing interests to declare
      The data used during the current study are available from the corresponding author upon reasonable request.
      This study was approved by the Institutional Ethics Committee of Deyang People's Hospital (approval number: 2021-04-019-K01) and performed in accordance with the Declaration of Helsinki. As this study was a retrospective study of anonymous data, informed consent was waived by the committee.

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