Sirolimus use and incidence of venous thromboembolism in cardiac transplant recipients

Abstract

Sirolimus is an immunosuppressive agent increasingly used in cardiac transplant recipients in the setting of allograft vasculopathy or worsening renal function. Recently, sirolimus has been associated with increased risk of venous thromboembolism (VTE) in lung transplant recipients. To investigate whether this association is also present in cardiac transplant recipients, we retrospectively reviewed the charts of 67 cardiac transplant recipients whose immunosuppressive regimen included sirolimus and 134 matched cardiac transplant recipients whose regimen did not include sirolimus. Rates of VTE were compared. Multivariable Cox proportional hazards models tested the association of sirolimus use with VTE. A higher incidence of VTE was seen in patients treated with vs. without sirolimus (8/67 [12%] vs. 9/134 [7%], log-rank statistic: 4.66, p=0.03). Lower body mass index (BMI) and total cholesterol levels were also associated with VTE (p<0.05). The association of sirolimus with VTE persisted when adjusting for BMI (hazard ratio [95% confidence interval]: 2.96 [1.13, 7.75], p=0.03) but not when adjusting for total cholesterol (p=0.08). These data suggest that sirolimus is associated with an increased risk of VTE in cardiac transplant recipients, a risk possibly mediated through comorbid conditions. Larger, more conclusive studies are needed. Until such studies are completed, a heightened level of awareness for VTE in cardiac transplant recipients treated with sirolimus appears warranted.

Incidence of Venous Thromboembolism and Benefits and Risks of Thromboprophylaxis After Cardiac Surgery: A Systematic Review and Meta‐Analysis

“…The majority of the studies were observational studies (n=49), 16 studies were RCTs, and 3 were meta‐analyses (Tables 1 and 2). 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 Of the 16 RCTs identified,1...…”

Venous thromboembolism in heart transplant recipients: Incidence, recurrence and predisposing factors

“…With variable follow-up duration among studies, the reported cumulative incidence of VTE varied between 4.5% and 9.1% in kidney transplant recipients, 3-6 between 8.6% and 29% in lung transplant recipients, 7-10 and between 0.4% and 4.6% in liver transplant recipients. [11][12][13] In a single-center observational study 14 including 67 HT recipients treated with a sirolimus-based immunosuppressive regimen and 134 HT matched controls, the cumulative incidence of VTE during a mean follow-up of more than 3 years was 8.5%. Hypercoagulability secondary to chronic immunosuppressive therapy is thought to play an important role in the increased thromboembolic risk of solid-organ transplant recipients.…”

“…17 To the best of our knowledge, only one published original paper 14 has addressed the occurrence of VTE after HT. The authors of that study 14 focused specifically on the role of sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, as a risk factor for VTE. The purpose of our study was to describe the cumulative incidence and recurrence risk of VTE in HT recipients and to identify predisposing factors.…”

“…[3][4][5][6][7][8][9][10][11][12][13][14] In 2 large population-based cohorts from United Kingdom 15 and Canada, 16 the estimated incidence rates of VTE among individuals from the general population were, respectively, 1.33 and 1.22 cases per 1,000 persons-years, decreasing to 1.07 cases per 1,000 persons-years when cancer-related VTE episodes were excluded. 15 With variable follow-up duration among studies, the reported cumulative incidence of VTE varied between 4.5% and 9.1% in kidney transplant recipients, 3-6 between 8.6% and 29% in lung transplant recipients, 7-10 and between 0.4% and 4.6 % in liver transplant recipients.…”

Effects of Immunosuppressive agents on neutrophils inflammatory response in humans: An inflammatory perspective on coronary allograft vasculopathy

“…However, mTOR inhibitors may have some deleterious effects on human vasculature. For instance, SIR treatment increased the risk of venous thromboembolism [28,108] and long-term treatment with EVE has been associated with a significant increase in necrotic and calcified tissue in the human cardiac allograft [109] . Nevertheless, most of the biologic differences between SIR and EVE remain largely unknown.…”