© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2015: 29: 629–635 DOI: 10.1111/ctr.12566
Clinical Transplantation
Risk of deep vein thrombosis and pulmonary embolism after heart transplantation: clinical outcomes comparing upper extremity deep vein thrombosis and lower extremity deep vein thrombosis Elboudwarej O, Patel JK, Liou F, Rafiei M, Osborne A, Chai W, Kittleson M, Czer L, Stern L, Esmailian F, Kobashigawa JA. Risk of deep vein thrombosis and pulmonary embolism after heart transplantation: clinical outcomes comparing upper extremity deep vein thrombosis and lower extremity deep vein thrombosis. Abstract: Introduction: Heart transplant patients have risk factors that place them at higher risk for acute venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), than the general population. We assessed for rate of VTE and incidence of PE-related mortality among heart transplant patients. Materials and Methods: A total of 1258 heart transplant patients were evaluated for the development of VTE. The diagnosis of DVT was made by Duplex ultrasonography, and PE was diagnosed by computerized tomography pulmonary angiography or ventilation–perfusion radionuclide scan. PE-related mortality was assessed at one yr, three yr, and five yr post-transplant. Results: A total of 117 (9.3%) patients were diagnosed with DVT, including 65 of 117 (55.5%) with lower extremity DVT (LEDVT) and 52 of 117 (44.4%) with upper extremity DVT (UEDVT). A total of 24 (1.9%) patients experienced PE with seven (29.2%) resulting deaths. The rate of LEDVT and UEDVT was similar (55.5% vs. 44.4%); however, the incidence of PE was greater for those with LEDVT (23.1% vs. 7.7%; p = 0.04). Patients with PE had lower survival over the five-yr follow-up period compared to those with DVT only (67% vs. 81%; p = 0.51). Conclusion: Heart transplant patients have a high incidence of VTE despite current best practice, indicating a need for a more aggressive approach to thromboprophylaxis.
Acute venous thromboembolism (VTE), which encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE), has an annual incidence of approximately one or two cases per 1000 persons in the general population and is a leading cause of cardiovascular-related mortality (1–3). Heart transplant patients have risk factors that make them particularly susceptible to VTE. The disruption of the vascular endothelium from repeated access for heart biopsies is a major risk factor for thromboembolic events. Heart transplant recipients also have prothrombotic hemostatic changes that include increased platelet activation, reduced fibrinolysis, and increased pro-inflammatory mark-
Omeed Elboudwarej, Jignesh K. Patel, Frank Liou, Matthew Rafiei, Ashley Osborne, Wanxing Chai, Michelle Kittleson, Lawrence Czer, Lily Stern, Fardad Esmailian and Jon A. Kobashigawa Cedars-Sinai Heart Institute, Los Angeles, CA, USA
Key words: deep vein thrombosis – heart transplantation – pulmonary embolism – transplants – venous thromboembolism Corresponding author: Jignesh K. Patel, MD, PhD, Cedars-Sinai Heart Institute, 8536 Wilshire Blvd #301, Beverly Hills, CA 90211, USA. Tel.: +1 310 248 8300; fax: +1 310 248 8333; e-mail: [email protected] Conflict of interest: None. Accepted for publication 13 May 2015
ers that have been associated with the development of transplant coronary artery disease (4–8). These hemodynamic abnormalities are exacerbated by the need for central venous catheter placement for UNOS status 1A patients awaiting heart transplant, immobility from bed rest in the often-prolonged pre-operative period, and need for repeat endomyocardial biopsies after transplant for rejection surveillance. To date, no studies have compared how upper extremity DVT (UEDVT) as compared to lower extremity DVT (LEDVT) affect outcomes in heart transplant patients. While UEDVT has traditionally been considered a less serious complication
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than LEDVT, it remains a significant clinical problem and has been found to cause PE in up to one-third of patients (9). UEDVT may occur in anywhere from 5 to 45% of patients and account for 10% of all DVT (10). Central venous catheter use, which is the primary risk factor for UEDVT, is now more routinely used in medical practice and will likely increase the incidence of UEDVT (11– 14). The majority of heart transplant recipients have also had placement of transvenous cardiac defibrillators prior to transplant. The devices are generally removed at the time of transplant, and in most cases, the transvenous pacing leads are also removed. However, in many cases, due to extensive fibrosis, remnants of these leads may be left behind and these may also serve as a nidus for UEDVT. The aim of this study was to identify the incidence of VTE in a heart transplant patient population from a single center and determine how rates of PE-associated mortality differed between UEDVT and LEDVT.
stopped 3 days before each endomyocardial biopsy and resumed the day of the biopsy. Patients with a known hypercoagulable state were bridged with enoxaparin. All patients received triple-drug immunosuppression regimen of a calcineurin inhibitor (cyclosporine or tacrolimus), antiproliferative (azathioprine, mycophenolate mofetil, or everolimus), and corticosteroid (prednisone) at baseline following heart transplantation. All patients receive routine aspirin 81 mg daily prophylaxis post-transplant unless contraindicated. Statistical methods
Normally distributed continuous variables were compared across two groups using the independent samples t-test and were reported as mean standard deviation. Categorical variables were summarized by frequency and percent and were compared using Fisher’s exact test. All analyses were conducted in SPSS version 18.0 (SPSS, Chicago, IL, USA). A p-value < 0.05 was considered significant.
Materials and Methods Study population
Results
Between January 1994 and August 2011, 1258 heart transplant patients were evaluated for development of VTE. The mean follow-up period was 5.4 4.3 yr. A retrospective comprehensive chart review was performed, and the institutional review board of Cedars-Sinai Medical Center approved the study. Following heart transplant, all patients were administered VTE prophylaxis with subcutaneous unfractionated heparin and/or compression stockings. The diagnosis of DVT was made by Duplex ultrasonography in symptomatic patients or in patients with a clinical suspicion for DVT. For the purposes of the study, the UE deep veins included the axillary, subclavian and internal jugular veins, and LE deep veins included the femoral, profunda, popliteal, peroneal, and tibial veins. Pulmonary embolism was diagnosed by computerized tomography pulmonary angiography or by ventilation– perfusion radionuclide scan. For patients with a diagnosis of VTE, anticoagulation was initiated in the first month following heart transplant with subcutaneous enoxaparin due to the need for repeat endomyocardial biopsies in the early posttransplant period. Patients with contraindications for enoxaparin and LEDVT received an IVC filter. After the first month following transplant, patients could be initiated on warfarin adjusted to maintain an international normalized ratio (INR) between 2 and 3. For these patients, anticoagulation was
Of the 1248 heart transplant patients evaluated, 117 (9.3%) were diagnosed with DVT, among whom 65 of 117 (55.5%) had LEDVT and 52 of 117 (44.4%) had UEDVT. One patient had a DVT in both upper and lower extremities and was included as part of the UEDVT group in all analyses. The median time from transplant to development of DVT was 4.46 months (range 0.04–189.6). A total of 24 (1.9%) patients experienced PE. The baseline characteristics of these patients are shown in Table 1. The statistically significant differences found between patients who had UEDVT compared to LEDVT were donor age (38.0 12.4 vs. 32.1 12.7; p = 0.01) and recipient body mass index (24.3 3.6 vs. 26.4 4.6; p = 0.01). In comparison with all heart transplant patients, those with LEDVT were more likely to have a higher recipient age (58.9 10.6 vs. 55.6 12.0; p = 0.03) and body mass index (26.4 4.6 vs. 25.1 4.5; p = 0.02). The single difference between all heart transplant patients and those with UEDVT was the higher donor age in the latter group (38.0 12.4 vs. 32.4 13.0; p = 0.002). Of the 24 patients with PE, 38% were status 1 at the time of listing. The immunosuppressant regimen for each patient following heart transplantation is listed in Table 2. Compared to all patients without VTE, those with UEDVT were more likely to be on combination of tacrolimus/mycophenolate mofetil
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DVT and PE risk after heart transplant Table 1. Baseline characteristics
Demographics Recipient age, mean yr SD Donor age, mean yr SD % Female Ischemic time Mean min SD Body mass index Mean kg/m2 SD % Status 1 at listing Primary reason for transplantation, Coronary artery disease as underlying diagnosis (%) Insertion of ventricular assist device (%) Diabetes mellitus (%)
All patients without DVT or PE (N = 1131)
Upper DVT (N = 52)
Lower DVT (N = 65)
PE (N = 24)
55.6 12.0 32.4 13.0 24% 187.4 70.5
58.7 11.9 38.0 12.4* 33% 180.0 67.8
58.9 10.6* 32.1 12.7** 29% 180.1 66.5
57.9 10.8 35.3 14.5 17% 207.9 69.4
25.1 4.5
24.3 3.6
26.4 4.6*,**
25.8 4.7
43% 48%
48% 54%
50% 54%
32% 46%
11% 22%
15% 15%
14% 21%
13% 19%
*p < 0.05 compared to the all patients group. **p < 0.05 compared to the upper DVT group. ***p < 0.05 compared to the lower DVT group.
(56% vs. 31%; p < 0.001) and less likely to be on tacrolimus/azathioprine (3% vs. 12%; p = 0.03) and cyclosporine/azathioprine (10% vs. 34%; p < 0.001). Patients with LEDVT were also more likely to be on tacrolimus/mycophenolate mofetil (54% vs. 31%; p < 0.001) and cyclosporine/mycophenolate mofetil (29% vs. 18%; p = 0.05) as well as a proliferation signal inhibitor at any time posttransplant (45% vs. 29%; p = 0.01) compared to all patients; LEDVT patients were less likely to be on a regimen of tacrolimus/azathioprine (2% vs. 12%; p = 0.01) and cyclosporine/azathioprine (12% vs. 34%; p < 0.001). Patients who developed PE were significantly more likely to be on cyclosporine/mycophenolate mofetil (38% vs. 18%; p = 0.03) as well as a proliferation signal inhibitor at any time post-transplant (54% vs. 29%; p = 0.01). The majority of patients with DVT were treated with heparin, enoxaparin, or argatroban, including 25 of 52 patients (48.1%) with UEDVT and 28 of 65 (43.1%) with LEDVT (see
Table 3). Among patients with LEDVT, 13 of 65 (20%) had an IVC filter placed as part of their treatment course. Although the rate of LEDVT and UEDVT was comparable (55.5% vs. 44.4%), the incidence of PE was greater for those with LEDVT (23.1% vs. 7.7%; p = 0.04). Among patients who had PE, the primary treatment type at the time of the thromboembolic event was heparin, enoxaparin, or argatroban, regardless of the type of DVT (see Table 4). No patients had an IVC filter placed as part of their treatment course. Among patients who died without documented antithrombotic treatment, three had an existing LEDVT and two had no documented DVT. Overall, seven of 24 (29.2%) patients died from PE-related complications of whom four had LEDVT and three had no prior DVT identified. The actuarial survival rate among patients with VTE is documented in Table 5. At the three-yr and five-yr time interval post-transplant, patients with PE had relatively lower survival rates than both
Table 2. Baseline immunosuppressive regimens for cardiac transplant patients with venous thromboembolism Baseline immunosuppression
All patients without VTE (n = 1131)
UEDVT* (n = 52)
LEDVT (n = 65)
PE (n = 24)
TAC/MMF, n (%) TAC/AZA, n (%) CSA/MMF, n (%) CSA/AZA, n (%) CSA/RAD, n (%) PSI anytime post-transplant, n (%)
197/628 (31%) 73/628 (12%) 113/628 (18%) 211/628 (34%) 30/628 (5%) 182/628 (29%)
30 (58%)¶ 1 (3%)¶ 15 (29%) 5 (10%) 1 (3%) 19 (37%)
36 (55%)¶ 1 (2%)¶ 19 (29%)¶ 8 (12%)¶ 1 (2%) 29 (45%)¶
11 (46%) 0 (0%) 9 (38%)¶ 4 (17%) 0 (0%) 13 (54%)¶
AZA, azathioprine; CSA, cyclosporine; LEDVT, lower extremity deep vein thrombosis; MMF, mycophenolate mofetil; PE, pulmonary embolism; PSA, proliferation signal inhibitors; RAD, everolimus; UEDVT, upper extremity deep vein thrombosis; TAC, tacrolimus; VTE, venous thromboembolism. *Includes one patient with both UEDVT and LEDVT. ¶ p < 0.05 compared to “all patients without VTE” group.
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Elboudwarej et al. Table 3. Treatments rendered among all heart transplant patients with deep vein thrombosis
Table 5. Actuarial survival following heart transplant in patients with and without venous thromboembolism
Treatment type
UEDVT* (n = 52)
LEDVT (n = 65)
Actuarial survival
Control (n = 1131)
UEDVT* (n = 48)
LEDVT (n = 50)
PE (n = 24)
Log rank p-value
No treatment Heparin/enoxaparin/argatroban Warfarin IVC filter Heparin + IVC filter Heparin + warfarin Heparin + aspirin Heparin + surgical embolectomy Warfarin + IVC filter Aspirin + clopidogrel Unknown
7 25 11 0 0 3 1 1 1 1 1
9 28 10 10 1 3 0 0 2 0 1
1-yr 2 yr 3 yr
90% 82% 78%
90% 85% 81%
98% 86% 82%
92% 79% 67%
0.29 0.79 0.51
LEDVT, lower extremity deep vein thrombosis; PE, pulmonary embolism; UEDVT, upper extremity deep vein thrombosis. *Includes one patient with both UE DVT and LE DVT.
LEDVT, lower extremity deep vein thrombosis; UEDVT, upper extremity deep vein thrombosis. *Includes one patient with both UEDVT and LEDVT.
Table 4. Treatments rendered among all heart transplant patients with pulmonary embolism
Treatment type
PE and UEDVT* (n = 4)
PE and LEDVT (n = 15)
PE and No DVT (n = 5)
No treatment Heparin/enoxaparin/argatroban Warfarin IVC filter Heparin + warfarin Unknown Died without treatment
0 2 0 0 1 1 0
1 7 1 0 1 2 3
0 2 1 0 0 0 2
LEDVT, lower extremity deep vein thrombosis; PE, pulmonary embolism; UEDVT, upper extremity deep vein thrombosis. *Includes one patient with both UEDVT and LEDVT.
the LEDVT and UEDVT groups, but statistical significance was not reached (see Fig. 1). Discussion
This study shows that PE following heart transplantation remains a significant cause of morbidity and mortality despite use of thromboprophylactic regimens. In particular, we found that LEDVT poses a high risk for PE and death, findings that are consistent with prior studies that show relatively higher rates of symptomatic PE in patients with LEDVT (15, 16). The development of PE was associated with a higher mortality over the five-yr follow-up period compared to those with DVT only, consistent with previous studies (17, 18). Few trials have investigated the incidence of VTE following heart transplant. Forrat et al. found that the probability of developing thromboembolic complications post-cardiac transplant was
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Fig. 1. Kaplan–Meier survival curve of actuarial survival of patients with and without venous thromboembolism over fiveyr period (p>0.05 for all groups).
9.86 per 100 patients per year, with a 3.97% probability of fatal complications annually (19). A 2001 retrospective study examining thrombotic complications in heart transplant patients treated postoperatively with antiplatelet regimens found that 18% of patients had evidence of either arterial or venous thrombosis, with no statistically significant difference in overall mortality relative to the control group (20). Most recently, a single-center cohort of 635 heart transplant patients followed for a median post-transplant period of 8.4 yr had incidence rates of VTE, DVT, and PE of 12.7, 8.4, and 7.0 episodes per 1000 patient-years (21). With regard to incidence of VTE in other agematched patient populations, studies involving heart failure patients have shown highly variable results, with a frequency of DVT that varies from 10% to 59% and a PE frequency of 0.9–39% (22– 26). In non-hospitalized populations with heart
DVT and PE risk after heart transplant failure, the odds ratio for PE is three-fold higher compared to controls, with a relative smaller increase in the risk of DVT (27, 28). Our heart transplant population had a VTE incidence of 9.3% that is similar to the 8.5% incidence in the recent observational study by Alvarez-Alvarez et al. (21). There remains considerable debate as to the optimal treatment of UEDVT as large randomized controlled trials are lacking (29). The 2012 American College of Chest Physicians guideline recommendation is initial treatment with therapeutic doses of low molecular weight heparin, unfractionated heparin or fondaparinux in acute UEDVT involving the axillary or more proximal veins (Grade 1B Recommendation) (30). Mu~ noz et al. did a prospective study of 11 564 non-transplant patients with VTE and found that 9% of patients with UEDVT had symptomatic PE at presentation compared to 29% of patients with LEDVT (14). However, the rate of new PEs during follow-up was similar, and those with UEDVT had higher three-month mortality (11% vs. 7%; odds ratio, 1.58; 95% CI, 1.18–2.11). In our study, the overall rate of post-transplant DVT was not insignificant at 9.3%, with an overall rate of PE of 1.9%. Postsurgical use of clotting factors, such as factor VII and factor IX complex, may contribute to the development of VTE, particularly in the early post-transplant phase. Over 44% of heart transplant patients with DVT had UEDVT, of whom 7.7% suffered a PE. None of these patients died as a result of complications from UEDVT. In contrast, LEDVT was more common (55%) and associated a significantly higher rate of PE (23%). Mortality was only observed in patients with PE from LEDVT. This may be due to the higher clot burden emanating from LE veins and greater potential for embolization as a result of increased patient mobility. In particular, patients have the highest risk of VTE in the first year post-transplant as the median time to onset of VTE in our population was 4.5 months post-transplant. This may reflect the need for frequent scheduled endomyocardial biopsies that pose a risk factor for VTE, including 10 biopsies by six months post-transplant and 13 biopsies by 12 months post-transplant in our program. In our study, older and heavier heart transplant recipients appeared to be at greater risk for developing LEDVT, while the use of older donors was associated with the development of UEDVT. An additional risk factor for VTE is the need for maintenance immunosuppressive drugs that may have prothrombotic side effects (31, 32). Patients who were treated with proliferation signal inhibi-
tors at any time post-transplant, such as everolimus and sirolimus, were significantly more likely to develop PE compared to all patients (54% vs. 29%; p = 0.01). A retrospective study of 67 heart transplant patients on sirolimus showed a higher incidence of VTE (12% vs. 7%; p = 0.03) than patients whose regimen did not include sirolimus, but this finding was not statistically significant after adjustment for risk factors (33). Treatment with everolimus has been shown to lead to impaired fibrinolysis, increased thrombin formation, and endothelial activation (34). Additionally, the combination therapy of cyclosporine and mycophenolate mofetil has also been implicated in higher incidence of PE (38% vs. 18%; p = 0.03), and cyclosporine has been associated with an increased risk of thromboembolic complications, in part through platelet activation and accelerated thrombin formation (35, 36). The association of proliferation signal inhibitors with peripheral edema presents an increased risk for VTE as well. The high incidence of VTE after heart transplantation suggests that current standards for thromboprophylaxis may be inadequate. There are currently no guidelines for optimal management of VTE from the International Society of Heart and Lung Transplantation (37). Potential alternatives include longer-term prophylaxis, closer surveillance, increased intensity of current regimens, or transition to novel anticoagulants (direct thrombin inhibitors or factor Xa inhibitors). Current outpatient treatment with warfarin presents a challenge given the need for frequent surveillance biopsies particularly in the early post-transplant period, drug–drug, and food–drug interactions (38). Furthermore, optimal length of treatment following the first episode of VTE in the transplant population remains unknown. In the general population, recurrence rate is 10% annually irrespective of the duration of warfarin therapy (39). Among heart transplant patients, the incidence rate of VTE recurrence has been shown to be 30.5 (95% CI 13.2–60.2) episodes per 1000 patient-years, mostly in patients in whom oral anticoagulation had been completed (21). While treatment with warfarin post-VTE has been shown to strongly reduce the VTE recurrence rate, it is not associated with reduction in mortality and an elevated risk for major bleeding remains (40). There is evidence to show that continuation of low-dose aspirin following completion of anticoagulant therapy reduces the rate of VTE recurrence without increased risk of major bleed (41). Novel oral anticoagulants show promise in mitigating these complications by being administered in fixed doses without need for laboratory
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monitoring and fewer interactions with other agents. Multiple randomized clinical trials have shown dabigatran, a direct thrombin inhibitor, and rivaroxaban, a factor Xa inhibitor, to be as effective as warfarin in treating acute VTE with no significant difference in all-cause mortality or VTE-related mortality (42–45). A systematic review of four randomized trials comparing apixaban, a direct factor Xa inhibitor, vs. enoxaparin following total hip or knee replacement found that the risk of VTE was similar with no increase in incidence of significant bleeding (46). Only rivaroxaban, apixaban and edoxaban have been approved in the United States to date for use in VTE prophylaxis or treatment. The use of these agents in the heart transplant population, however, may be limited by frequently observed renal insufficiency, which also limits the use of low molecular weight heparins. This study has limitations inherent to a retrospective analysis involving a single center. Prospective multicenter studies are necessary to validate these findings. Additionally, while there are multiple studies to date examining thromboprophylaxis regimens, additional analysis is required studying optimal management and outcomes in the post-heart transplant population. The finding that actuarial survival was higher in patients with DVT than the control group may reflect more frequent follow-up and surveillance by physicians in response to the post-transplant complication, but definitive conclusions cannot be drawn given that the survival comparison between the two groups did not reach statistical significance. The sample size of the study also limits its statistical power to detect weaker risk factors for venous thromboembolism. We additionally lack data about whether the 117 patients found to have DVT had additional health risk factors that include prior history of DVT, inherited coagulopathies, immobilization, or use of hormonal therapy. In conclusion, the high incidence of VTE in heart transplant patients despite current best practice highlights the need for a more aggressive thromboprophylactic approach. The development of LEDVT appears to significantly increase the risk of PE compared to UEDVT, and the development of PE is associated with a high mortality. Larger studies are needed to delineate risk factors that may predispose patients to VTE so that therapies can be better targeted. Furthermore, randomized trials will be needed to investigate whether novel oral anticoagulants may lead to improved outcomes in the post-transplant period compared to current available therapies.
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Authors’ contributions
Omeed Elboudwarej involved in the data collection, data analysis, and drafting of the manuscript. Jignesh Patel contributed to the concept/design, critical revision, and approval of the manuscript. Frank Liou involved in the data collection and statistics. Matthew Rafiei and Ashley Osborne contributed to statistics. Wanxing Chai helped in data collection. Michelle Kittleson, Lawrence Czer, Lily Stern, and Fardad Esmailian helped in other aspects. Jon Kobashigawa contributed to the critical revision and approval of the manuscript. References 1. MACKMAN N. Triggers, targets and treatments for thrombosis. Nature 2008: 451: 914. 2. OGER E. Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group. Groupe d’Etude de la Thrombose de Bretagne Occidentale. Thromb Haemost 2000: 83: 657. 3. SPENCER FA, EMERY C, LESSARD D et al. The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med 2006: 21: 722. 4. BENZA RL, CAVENDER MA, BARCHUE J et al. Alterations in the fibrinolytic cascade post-transplant: evidence of a bimodal expression pattern. J Heart Lung Transplant 2007: 26: 494. 5. CUGNO M, MARI D, MERONI PL et al. Haemostatic and inflammatory biomarkers in advanced chronic heart failure: role of oral anticoagulants and successful heart transplantation. Br J Haematol 2004: 126: 85. 6. HOGNESTAD A, MICHELSEN A, BROSSTAD F et al. Platelet activation in heart transplant recipients. Clin Transplant 2004: 18: 142. 7. HOLM T, AUKRUST P, ANDREASSEN AK et al. Peripheral endothelial dysfunction in heart transplant recipients: possible role of proinflammatory cytokines. Clin Transplant 2000: 14: 218. 8. HUNT BJ, SEGAL H, YACOUB M. Hemostatic changes in heart transplant recipients and their relationship to accelerated coronary sclerosis. Transplantation 1993: 55: 309. 9. PRANDONI P, POLISTENA P, BERNARDI E et al. Upperextremity deep vein thrombosis. Risk factors, diagnosis, and complications. Arch Intern Med 1997: 157: 57. 10. KUCHER N. Clinical practice. Deep-vein thrombosis of the upper extremities. N Engl J Med 2011: 364: 861. 11. ALLEN AW, MEGARGELL JL, BROWN DB et al. Venous thrombosis associated with the placement of peripherally inserted central catheters. J Vasc Interv Radiol 2000: 11: 1309. 12. HORNE MK 3rd, MAY DJ, ALEXANDER HR et al. Venographic surveillance of tunneled venous access devices in adult oncology patients. Ann Surg Oncol 1995: 2: 174. 13. LOBO BL, VAIDEAN G, BROYLES J, REAVES AB, SHORR RI. Risk of venous thromboembolism in hospitalized patients with peripherally inserted central catheters. J Hosp Med 2009: 4: 417. 14. MUNOZ FJ, MISMETTI P, POGGIO R et al. Clinical outcome of patients with upper-extremity deep vein thrombosis: results from the RIETE registry. Chest 2008: 133: 143.
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31. PUSCHEL A, LINDENBLATT N, KATZFUSS J, VOLLMAR B, KLAR E. Immunosuppressants accelerate microvascular thrombus formation in vivo: role of endothelial cell activation. Surgery 2012: 151: 26. 32. SAIKALI JA, TRUONG LD, SUKI WN. Sirolimus may promote thrombotic microangiopathy. Am J Transplant 2003: 3: 229. 33. THIBODEAU JT, MISHKIN JD, PATEL PC et al. Sirolimus use and incidence of venous thromboembolism in cardiac transplant recipients. Clin Transplant 2012: 26: 953. 34. BAAS MC, GERDES VE, TEN BERGE IJ et al. Treatment with everolimus is associated with a procoagulant state. Thromb Res 2013: 132: 307. 35. BRUNKWALL J, BERGQVIST D, BERGENTZ SE, BORNMYR S, HUSBERG B. Postoperative deep venous thrombosis after renal transplantation. Effects of cyclosporine. Transplantation 1987: 43: 647. 36. TOMASIAK M, RUSAK T, GACKO M, STELMACH H. Cyclosporine enhances platelet procoagulant activity. Nephrol Dial Transplant 2007: 22: 1750. 37. COSTANZO MR, DIPCHAND A, STARLING R et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010: 29: 914. 38. KEARON C, KAHN SR, AGNELLI G, GOLDHABER S, RASKOB GE, COMEROTA AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008: 133(6 Suppl): 454S. 39. BAGLIN T, PALMER CR, LUDDINGTON R, BAGLIN C. Unprovoked recurrent venous thrombosis: prediction by Ddimer and clinical risk factors. J Thromb Haemost 2008: 6: 577. 40. MIDDELDORP S, PRINS MH, HUTTEN BA. Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism. Cochrane Database Syst Rev 2014: 8: CD001367. 41. BECATTINI C, AGNELLI G, SCHENONE A et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012: 366: 1959. 42. BAUERSACHS R, BERKOWITZ SD, BRENNER B et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010: 363: 2499. 43. ROMUALDI E, DONADINI MP, AGENO W. Oral rivaroxaban after symptomatic venous thromboembolism: the continued treatment study (EINSTEIN-extension study). Expert Rev Cardiovasc Ther 2011: 9: 841. 44. SCHULMAN S, KEARON C, KAKKAR AK et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009: 361: 2342. 45. SCHULMAN S, KEARON C, KAKKAR AK et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013: 368: 709. 46. NIETO JA, ESPADA NG, MERINO RG, GONZALEZ TC. Dabigatran, rivaroxaban and apixaban versus enoxaparin for thomboprophylaxis after total knee or hip arthroplasty: pool-analysis of phase III randomized clinical trials. Thromb Res 2012: 130: 183.
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Clin Transplant 2015: 29: 629–635 DOI: 10.1111/ctr.12566
Clinical Transplantation
Risk of deep vein thrombosis and pulmonary embolism after heart transplantation: clinical outcomes comparing upper extremity deep vein thrombosis and lower extremity deep vein thrombosis Elboudwarej O, Patel JK, Liou F, Rafiei M, Osborne A, Chai W, Kittleson M, Czer L, Stern L, Esmailian F, Kobashigawa JA. Risk of deep vein thrombosis and pulmonary embolism after heart transplantation: clinical outcomes comparing upper extremity deep vein thrombosis and lower extremity deep vein thrombosis. Abstract: Introduction: Heart transplant patients have risk factors that place them at higher risk for acute venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), than the general population. We assessed for rate of VTE and incidence of PE-related mortality among heart transplant patients. Materials and Methods: A total of 1258 heart transplant patients were evaluated for the development of VTE. The diagnosis of DVT was made by Duplex ultrasonography, and PE was diagnosed by computerized tomography pulmonary angiography or ventilation–perfusion radionuclide scan. PE-related mortality was assessed at one yr, three yr, and five yr post-transplant. Results: A total of 117 (9.3%) patients were diagnosed with DVT, including 65 of 117 (55.5%) with lower extremity DVT (LEDVT) and 52 of 117 (44.4%) with upper extremity DVT (UEDVT). A total of 24 (1.9%) patients experienced PE with seven (29.2%) resulting deaths. The rate of LEDVT and UEDVT was similar (55.5% vs. 44.4%); however, the incidence of PE was greater for those with LEDVT (23.1% vs. 7.7%; p = 0.04). Patients with PE had lower survival over the five-yr follow-up period compared to those with DVT only (67% vs. 81%; p = 0.51). Conclusion: Heart transplant patients have a high incidence of VTE despite current best practice, indicating a need for a more aggressive approach to thromboprophylaxis.
Acute venous thromboembolism (VTE), which encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE), has an annual incidence of approximately one or two cases per 1000 persons in the general population and is a leading cause of cardiovascular-related mortality (1–3). Heart transplant patients have risk factors that make them particularly susceptible to VTE. The disruption of the vascular endothelium from repeated access for heart biopsies is a major risk factor for thromboembolic events. Heart transplant recipients also have prothrombotic hemostatic changes that include increased platelet activation, reduced fibrinolysis, and increased pro-inflammatory mark-
Omeed Elboudwarej, Jignesh K. Patel, Frank Liou, Matthew Rafiei, Ashley Osborne, Wanxing Chai, Michelle Kittleson, Lawrence Czer, Lily Stern, Fardad Esmailian and Jon A. Kobashigawa Cedars-Sinai Heart Institute, Los Angeles, CA, USA
Key words: deep vein thrombosis – heart transplantation – pulmonary embolism – transplants – venous thromboembolism Corresponding author: Jignesh K. Patel, MD, PhD, Cedars-Sinai Heart Institute, 8536 Wilshire Blvd #301, Beverly Hills, CA 90211, USA. Tel.: +1 310 248 8300; fax: +1 310 248 8333; e-mail: [email protected] Conflict of interest: None. Accepted for publication 13 May 2015
ers that have been associated with the development of transplant coronary artery disease (4–8). These hemodynamic abnormalities are exacerbated by the need for central venous catheter placement for UNOS status 1A patients awaiting heart transplant, immobility from bed rest in the often-prolonged pre-operative period, and need for repeat endomyocardial biopsies after transplant for rejection surveillance. To date, no studies have compared how upper extremity DVT (UEDVT) as compared to lower extremity DVT (LEDVT) affect outcomes in heart transplant patients. While UEDVT has traditionally been considered a less serious complication
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than LEDVT, it remains a significant clinical problem and has been found to cause PE in up to one-third of patients (9). UEDVT may occur in anywhere from 5 to 45% of patients and account for 10% of all DVT (10). Central venous catheter use, which is the primary risk factor for UEDVT, is now more routinely used in medical practice and will likely increase the incidence of UEDVT (11– 14). The majority of heart transplant recipients have also had placement of transvenous cardiac defibrillators prior to transplant. The devices are generally removed at the time of transplant, and in most cases, the transvenous pacing leads are also removed. However, in many cases, due to extensive fibrosis, remnants of these leads may be left behind and these may also serve as a nidus for UEDVT. The aim of this study was to identify the incidence of VTE in a heart transplant patient population from a single center and determine how rates of PE-associated mortality differed between UEDVT and LEDVT.
stopped 3 days before each endomyocardial biopsy and resumed the day of the biopsy. Patients with a known hypercoagulable state were bridged with enoxaparin. All patients received triple-drug immunosuppression regimen of a calcineurin inhibitor (cyclosporine or tacrolimus), antiproliferative (azathioprine, mycophenolate mofetil, or everolimus), and corticosteroid (prednisone) at baseline following heart transplantation. All patients receive routine aspirin 81 mg daily prophylaxis post-transplant unless contraindicated. Statistical methods
Normally distributed continuous variables were compared across two groups using the independent samples t-test and were reported as mean standard deviation. Categorical variables were summarized by frequency and percent and were compared using Fisher’s exact test. All analyses were conducted in SPSS version 18.0 (SPSS, Chicago, IL, USA). A p-value < 0.05 was considered significant.
Materials and Methods Study population
Results
Between January 1994 and August 2011, 1258 heart transplant patients were evaluated for development of VTE. The mean follow-up period was 5.4 4.3 yr. A retrospective comprehensive chart review was performed, and the institutional review board of Cedars-Sinai Medical Center approved the study. Following heart transplant, all patients were administered VTE prophylaxis with subcutaneous unfractionated heparin and/or compression stockings. The diagnosis of DVT was made by Duplex ultrasonography in symptomatic patients or in patients with a clinical suspicion for DVT. For the purposes of the study, the UE deep veins included the axillary, subclavian and internal jugular veins, and LE deep veins included the femoral, profunda, popliteal, peroneal, and tibial veins. Pulmonary embolism was diagnosed by computerized tomography pulmonary angiography or by ventilation– perfusion radionuclide scan. For patients with a diagnosis of VTE, anticoagulation was initiated in the first month following heart transplant with subcutaneous enoxaparin due to the need for repeat endomyocardial biopsies in the early posttransplant period. Patients with contraindications for enoxaparin and LEDVT received an IVC filter. After the first month following transplant, patients could be initiated on warfarin adjusted to maintain an international normalized ratio (INR) between 2 and 3. For these patients, anticoagulation was
Of the 1248 heart transplant patients evaluated, 117 (9.3%) were diagnosed with DVT, among whom 65 of 117 (55.5%) had LEDVT and 52 of 117 (44.4%) had UEDVT. One patient had a DVT in both upper and lower extremities and was included as part of the UEDVT group in all analyses. The median time from transplant to development of DVT was 4.46 months (range 0.04–189.6). A total of 24 (1.9%) patients experienced PE. The baseline characteristics of these patients are shown in Table 1. The statistically significant differences found between patients who had UEDVT compared to LEDVT were donor age (38.0 12.4 vs. 32.1 12.7; p = 0.01) and recipient body mass index (24.3 3.6 vs. 26.4 4.6; p = 0.01). In comparison with all heart transplant patients, those with LEDVT were more likely to have a higher recipient age (58.9 10.6 vs. 55.6 12.0; p = 0.03) and body mass index (26.4 4.6 vs. 25.1 4.5; p = 0.02). The single difference between all heart transplant patients and those with UEDVT was the higher donor age in the latter group (38.0 12.4 vs. 32.4 13.0; p = 0.002). Of the 24 patients with PE, 38% were status 1 at the time of listing. The immunosuppressant regimen for each patient following heart transplantation is listed in Table 2. Compared to all patients without VTE, those with UEDVT were more likely to be on combination of tacrolimus/mycophenolate mofetil
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DVT and PE risk after heart transplant Table 1. Baseline characteristics
Demographics Recipient age, mean yr SD Donor age, mean yr SD % Female Ischemic time Mean min SD Body mass index Mean kg/m2 SD % Status 1 at listing Primary reason for transplantation, Coronary artery disease as underlying diagnosis (%) Insertion of ventricular assist device (%) Diabetes mellitus (%)
All patients without DVT or PE (N = 1131)
Upper DVT (N = 52)
Lower DVT (N = 65)
PE (N = 24)
55.6 12.0 32.4 13.0 24% 187.4 70.5
58.7 11.9 38.0 12.4* 33% 180.0 67.8
58.9 10.6* 32.1 12.7** 29% 180.1 66.5
57.9 10.8 35.3 14.5 17% 207.9 69.4
25.1 4.5
24.3 3.6
26.4 4.6*,**
25.8 4.7
43% 48%
48% 54%
50% 54%
32% 46%
11% 22%
15% 15%
14% 21%
13% 19%
*p < 0.05 compared to the all patients group. **p < 0.05 compared to the upper DVT group. ***p < 0.05 compared to the lower DVT group.
(56% vs. 31%; p < 0.001) and less likely to be on tacrolimus/azathioprine (3% vs. 12%; p = 0.03) and cyclosporine/azathioprine (10% vs. 34%; p < 0.001). Patients with LEDVT were also more likely to be on tacrolimus/mycophenolate mofetil (54% vs. 31%; p < 0.001) and cyclosporine/mycophenolate mofetil (29% vs. 18%; p = 0.05) as well as a proliferation signal inhibitor at any time posttransplant (45% vs. 29%; p = 0.01) compared to all patients; LEDVT patients were less likely to be on a regimen of tacrolimus/azathioprine (2% vs. 12%; p = 0.01) and cyclosporine/azathioprine (12% vs. 34%; p < 0.001). Patients who developed PE were significantly more likely to be on cyclosporine/mycophenolate mofetil (38% vs. 18%; p = 0.03) as well as a proliferation signal inhibitor at any time post-transplant (54% vs. 29%; p = 0.01). The majority of patients with DVT were treated with heparin, enoxaparin, or argatroban, including 25 of 52 patients (48.1%) with UEDVT and 28 of 65 (43.1%) with LEDVT (see
Table 3). Among patients with LEDVT, 13 of 65 (20%) had an IVC filter placed as part of their treatment course. Although the rate of LEDVT and UEDVT was comparable (55.5% vs. 44.4%), the incidence of PE was greater for those with LEDVT (23.1% vs. 7.7%; p = 0.04). Among patients who had PE, the primary treatment type at the time of the thromboembolic event was heparin, enoxaparin, or argatroban, regardless of the type of DVT (see Table 4). No patients had an IVC filter placed as part of their treatment course. Among patients who died without documented antithrombotic treatment, three had an existing LEDVT and two had no documented DVT. Overall, seven of 24 (29.2%) patients died from PE-related complications of whom four had LEDVT and three had no prior DVT identified. The actuarial survival rate among patients with VTE is documented in Table 5. At the three-yr and five-yr time interval post-transplant, patients with PE had relatively lower survival rates than both
Table 2. Baseline immunosuppressive regimens for cardiac transplant patients with venous thromboembolism Baseline immunosuppression
All patients without VTE (n = 1131)
UEDVT* (n = 52)
LEDVT (n = 65)
PE (n = 24)
TAC/MMF, n (%) TAC/AZA, n (%) CSA/MMF, n (%) CSA/AZA, n (%) CSA/RAD, n (%) PSI anytime post-transplant, n (%)
197/628 (31%) 73/628 (12%) 113/628 (18%) 211/628 (34%) 30/628 (5%) 182/628 (29%)
30 (58%)¶ 1 (3%)¶ 15 (29%) 5 (10%) 1 (3%) 19 (37%)
36 (55%)¶ 1 (2%)¶ 19 (29%)¶ 8 (12%)¶ 1 (2%) 29 (45%)¶
11 (46%) 0 (0%) 9 (38%)¶ 4 (17%) 0 (0%) 13 (54%)¶
AZA, azathioprine; CSA, cyclosporine; LEDVT, lower extremity deep vein thrombosis; MMF, mycophenolate mofetil; PE, pulmonary embolism; PSA, proliferation signal inhibitors; RAD, everolimus; UEDVT, upper extremity deep vein thrombosis; TAC, tacrolimus; VTE, venous thromboembolism. *Includes one patient with both UEDVT and LEDVT. ¶ p < 0.05 compared to “all patients without VTE” group.
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Elboudwarej et al. Table 3. Treatments rendered among all heart transplant patients with deep vein thrombosis
Table 5. Actuarial survival following heart transplant in patients with and without venous thromboembolism
Treatment type
UEDVT* (n = 52)
LEDVT (n = 65)
Actuarial survival
Control (n = 1131)
UEDVT* (n = 48)
LEDVT (n = 50)
PE (n = 24)
Log rank p-value
No treatment Heparin/enoxaparin/argatroban Warfarin IVC filter Heparin + IVC filter Heparin + warfarin Heparin + aspirin Heparin + surgical embolectomy Warfarin + IVC filter Aspirin + clopidogrel Unknown
7 25 11 0 0 3 1 1 1 1 1
9 28 10 10 1 3 0 0 2 0 1
1-yr 2 yr 3 yr
90% 82% 78%
90% 85% 81%
98% 86% 82%
92% 79% 67%
0.29 0.79 0.51
LEDVT, lower extremity deep vein thrombosis; PE, pulmonary embolism; UEDVT, upper extremity deep vein thrombosis. *Includes one patient with both UE DVT and LE DVT.
LEDVT, lower extremity deep vein thrombosis; UEDVT, upper extremity deep vein thrombosis. *Includes one patient with both UEDVT and LEDVT.
Table 4. Treatments rendered among all heart transplant patients with pulmonary embolism
Treatment type
PE and UEDVT* (n = 4)
PE and LEDVT (n = 15)
PE and No DVT (n = 5)
No treatment Heparin/enoxaparin/argatroban Warfarin IVC filter Heparin + warfarin Unknown Died without treatment
0 2 0 0 1 1 0
1 7 1 0 1 2 3
0 2 1 0 0 0 2
LEDVT, lower extremity deep vein thrombosis; PE, pulmonary embolism; UEDVT, upper extremity deep vein thrombosis. *Includes one patient with both UEDVT and LEDVT.
the LEDVT and UEDVT groups, but statistical significance was not reached (see Fig. 1). Discussion
This study shows that PE following heart transplantation remains a significant cause of morbidity and mortality despite use of thromboprophylactic regimens. In particular, we found that LEDVT poses a high risk for PE and death, findings that are consistent with prior studies that show relatively higher rates of symptomatic PE in patients with LEDVT (15, 16). The development of PE was associated with a higher mortality over the five-yr follow-up period compared to those with DVT only, consistent with previous studies (17, 18). Few trials have investigated the incidence of VTE following heart transplant. Forrat et al. found that the probability of developing thromboembolic complications post-cardiac transplant was
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Fig. 1. Kaplan–Meier survival curve of actuarial survival of patients with and without venous thromboembolism over fiveyr period (p>0.05 for all groups).
9.86 per 100 patients per year, with a 3.97% probability of fatal complications annually (19). A 2001 retrospective study examining thrombotic complications in heart transplant patients treated postoperatively with antiplatelet regimens found that 18% of patients had evidence of either arterial or venous thrombosis, with no statistically significant difference in overall mortality relative to the control group (20). Most recently, a single-center cohort of 635 heart transplant patients followed for a median post-transplant period of 8.4 yr had incidence rates of VTE, DVT, and PE of 12.7, 8.4, and 7.0 episodes per 1000 patient-years (21). With regard to incidence of VTE in other agematched patient populations, studies involving heart failure patients have shown highly variable results, with a frequency of DVT that varies from 10% to 59% and a PE frequency of 0.9–39% (22– 26). In non-hospitalized populations with heart
DVT and PE risk after heart transplant failure, the odds ratio for PE is three-fold higher compared to controls, with a relative smaller increase in the risk of DVT (27, 28). Our heart transplant population had a VTE incidence of 9.3% that is similar to the 8.5% incidence in the recent observational study by Alvarez-Alvarez et al. (21). There remains considerable debate as to the optimal treatment of UEDVT as large randomized controlled trials are lacking (29). The 2012 American College of Chest Physicians guideline recommendation is initial treatment with therapeutic doses of low molecular weight heparin, unfractionated heparin or fondaparinux in acute UEDVT involving the axillary or more proximal veins (Grade 1B Recommendation) (30). Mu~ noz et al. did a prospective study of 11 564 non-transplant patients with VTE and found that 9% of patients with UEDVT had symptomatic PE at presentation compared to 29% of patients with LEDVT (14). However, the rate of new PEs during follow-up was similar, and those with UEDVT had higher three-month mortality (11% vs. 7%; odds ratio, 1.58; 95% CI, 1.18–2.11). In our study, the overall rate of post-transplant DVT was not insignificant at 9.3%, with an overall rate of PE of 1.9%. Postsurgical use of clotting factors, such as factor VII and factor IX complex, may contribute to the development of VTE, particularly in the early post-transplant phase. Over 44% of heart transplant patients with DVT had UEDVT, of whom 7.7% suffered a PE. None of these patients died as a result of complications from UEDVT. In contrast, LEDVT was more common (55%) and associated a significantly higher rate of PE (23%). Mortality was only observed in patients with PE from LEDVT. This may be due to the higher clot burden emanating from LE veins and greater potential for embolization as a result of increased patient mobility. In particular, patients have the highest risk of VTE in the first year post-transplant as the median time to onset of VTE in our population was 4.5 months post-transplant. This may reflect the need for frequent scheduled endomyocardial biopsies that pose a risk factor for VTE, including 10 biopsies by six months post-transplant and 13 biopsies by 12 months post-transplant in our program. In our study, older and heavier heart transplant recipients appeared to be at greater risk for developing LEDVT, while the use of older donors was associated with the development of UEDVT. An additional risk factor for VTE is the need for maintenance immunosuppressive drugs that may have prothrombotic side effects (31, 32). Patients who were treated with proliferation signal inhibi-
tors at any time post-transplant, such as everolimus and sirolimus, were significantly more likely to develop PE compared to all patients (54% vs. 29%; p = 0.01). A retrospective study of 67 heart transplant patients on sirolimus showed a higher incidence of VTE (12% vs. 7%; p = 0.03) than patients whose regimen did not include sirolimus, but this finding was not statistically significant after adjustment for risk factors (33). Treatment with everolimus has been shown to lead to impaired fibrinolysis, increased thrombin formation, and endothelial activation (34). Additionally, the combination therapy of cyclosporine and mycophenolate mofetil has also been implicated in higher incidence of PE (38% vs. 18%; p = 0.03), and cyclosporine has been associated with an increased risk of thromboembolic complications, in part through platelet activation and accelerated thrombin formation (35, 36). The association of proliferation signal inhibitors with peripheral edema presents an increased risk for VTE as well. The high incidence of VTE after heart transplantation suggests that current standards for thromboprophylaxis may be inadequate. There are currently no guidelines for optimal management of VTE from the International Society of Heart and Lung Transplantation (37). Potential alternatives include longer-term prophylaxis, closer surveillance, increased intensity of current regimens, or transition to novel anticoagulants (direct thrombin inhibitors or factor Xa inhibitors). Current outpatient treatment with warfarin presents a challenge given the need for frequent surveillance biopsies particularly in the early post-transplant period, drug–drug, and food–drug interactions (38). Furthermore, optimal length of treatment following the first episode of VTE in the transplant population remains unknown. In the general population, recurrence rate is 10% annually irrespective of the duration of warfarin therapy (39). Among heart transplant patients, the incidence rate of VTE recurrence has been shown to be 30.5 (95% CI 13.2–60.2) episodes per 1000 patient-years, mostly in patients in whom oral anticoagulation had been completed (21). While treatment with warfarin post-VTE has been shown to strongly reduce the VTE recurrence rate, it is not associated with reduction in mortality and an elevated risk for major bleeding remains (40). There is evidence to show that continuation of low-dose aspirin following completion of anticoagulant therapy reduces the rate of VTE recurrence without increased risk of major bleed (41). Novel oral anticoagulants show promise in mitigating these complications by being administered in fixed doses without need for laboratory
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monitoring and fewer interactions with other agents. Multiple randomized clinical trials have shown dabigatran, a direct thrombin inhibitor, and rivaroxaban, a factor Xa inhibitor, to be as effective as warfarin in treating acute VTE with no significant difference in all-cause mortality or VTE-related mortality (42–45). A systematic review of four randomized trials comparing apixaban, a direct factor Xa inhibitor, vs. enoxaparin following total hip or knee replacement found that the risk of VTE was similar with no increase in incidence of significant bleeding (46). Only rivaroxaban, apixaban and edoxaban have been approved in the United States to date for use in VTE prophylaxis or treatment. The use of these agents in the heart transplant population, however, may be limited by frequently observed renal insufficiency, which also limits the use of low molecular weight heparins. This study has limitations inherent to a retrospective analysis involving a single center. Prospective multicenter studies are necessary to validate these findings. Additionally, while there are multiple studies to date examining thromboprophylaxis regimens, additional analysis is required studying optimal management and outcomes in the post-heart transplant population. The finding that actuarial survival was higher in patients with DVT than the control group may reflect more frequent follow-up and surveillance by physicians in response to the post-transplant complication, but definitive conclusions cannot be drawn given that the survival comparison between the two groups did not reach statistical significance. The sample size of the study also limits its statistical power to detect weaker risk factors for venous thromboembolism. We additionally lack data about whether the 117 patients found to have DVT had additional health risk factors that include prior history of DVT, inherited coagulopathies, immobilization, or use of hormonal therapy. In conclusion, the high incidence of VTE in heart transplant patients despite current best practice highlights the need for a more aggressive thromboprophylactic approach. The development of LEDVT appears to significantly increase the risk of PE compared to UEDVT, and the development of PE is associated with a high mortality. Larger studies are needed to delineate risk factors that may predispose patients to VTE so that therapies can be better targeted. Furthermore, randomized trials will be needed to investigate whether novel oral anticoagulants may lead to improved outcomes in the post-transplant period compared to current available therapies.
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Authors’ contributions
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