• calcineurin inhibitor;
  • CMV infection;
  • cyclosporine;
  • heart transplantation;
  • tacrolimus


  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Authors' contributions
  8. References

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in heart transplant (HTx). Our aim was to analyze the rate of CMV infection in HTx patients receiving treatment with cyclosporine (CsA) or tacrolimus (Tac). Ninety-five patients were randomized to receive either CsA (53.7%) or Tac (46.3%). We performed prophylaxis with valganciclovir in patients with the highest risk of CMV infection. We considered CMV infection as an increased viral load or the presence of CMV in histological samples. We analyzed baseline characteristics, CMV infection, and other complications. Event-free rates were calculated using the Kaplan-Meier method. There were no significant differences in baseline characteristics between both groups. CMV infection was detected in 31.6% of patients (in 66.7% due to asymptomatic replication). The group treated with Tac had a lower rate of CMV infection (15.9% vs. 45.1%, p = 0.002) and longer CMV infection-free survival time (1440 vs. 899 d, p = 0.001). No differences were observed in the complications analyzed in both groups. The independent risk factors for infection identified in the multivariate analysis were treatment with CsA and bacterial infections. This was the first study to demonstrate a lower rate of CMV infection in patients treated with Tac vs. those treated with CsA after HTx.

Heart transplantation (HTx) is the best therapeutic option for patients with end-stage heart failure in the absence of significant comorbidities. The need for immunosuppression to prevent graft rejection has numerous side effects, as increased susceptibility to infection.

Infections of any type are the leading cause of death in the first year of HTx once the post-operative period is over [1, 2]. Among these, viral infections are an important source of morbidity and mortality after HTx. The main pathogen is cytomegalovirus (CMV) [3-5]. This microorganism can cause disease both as a direct consequence of its viral replication and tissue invasion (local or systemic infection), and through longer-term immunological mechanisms such as renal dysfunction [6] or cardiac allograft vasculopathy (indirect effects) [7, 8].

According to the literature [7], the most important aspect in the management of CMV infection after HTx is its prophylaxis, and the main determining factors are the CMV serologies of the donor and recipient. Thus, and in general, prophylactic treatments against CMV are prescribed only in high-risk cases, choosing a close follow-up in the rest [9-11].

Maintenance immunosuppressive medication does not alter the management of therapy against CMV, despite the fact that a lower rate of CMV infection was observed with azathioprine (vs. mycophenolate mofetil) [12, 13], and in patients receiving proliferation signal inhibitors (PSIs), regardless of the rest of immunosuppressive treatment [14, 15]. However, azathioprine is no longer used due to its adverse effects and the better tolerability and efficacy of mycophenolate mofetil (MMF). PSIs are a second-line immunosuppressive treatment in HTx. Thus, the standard immunosuppressive therapy is based on a calcineurin inhibitor (CNI) (cyclosporine or tacrolimus), MMF, and steroids.

In a recent comparative study of both CNI [16], our group observed that cyclosporine (CsA) was associated with a higher number of viral infections compared with tacrolimus (Tac). In view of these results, the aim of our study was to analyze the rate of CMV infection in our population of HTx patients according to the CNI used: CsA or Tac.

Materials and methods

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Authors' contributions
  8. References

From November 2006 to December 2009, 111 HTx were performed in our center. Patients with heart-lung transplants (2), retransplants (4), those who were not treated with a CNI due to persistent renal dysfunction, and those who died before starting treatment with a CNI (10) were excluded. The rest of patients were included in the study. Patients were randomized at the time of transplantation using a computer program to receive CsA or Tac. The total number of patients included in the study was 95: 53.7% were treated with CsA and 46.3% with Tac.

The study was conducted in accordance with the Declaration of Helsinki and was approved by the biomedical research ethics committee of our hospital. All patients signed informed consent.

Calcineurin inhibitors were introduced on post-operative day 2–3 after hemodynamic stabilization and improvement of renal function. CsA levels were maintained between 200 and 300 ng/mL for the first six months of treatment, and subsequently between 100 and 200 ng/mL. Tac plasma levels were initially maintained between 10 and 15 ng/mL and after six months between 5 and 10 ng/mL. All patients received intraoperative steroids, and subsequently induction with daclizumab/basiliximab, as well as maintenance with MMF and steroids with gradual dose reduction during the first year after transplant. The dose of MMF was 1 g/12 h from the second day on which levels were obtained but was not adjusted to them. In case of neutropenia or gastrointestinal complications, MMF was reduced to 500 mg/8 h.

Patients at higher risk of CMV infection (IgG-CMV-positive donors and IgG-CMV-negative recipients [D+/R−]) received prophylaxis with valganciclovir 900 mg/day for three months. In patients with progressive elevation of CMV viral load, preemptive therapy with valganciclovir 900 mg/12 h was prescribed for three wk, whereas in patients with a diagnosis of CMV disease, treatment was valganciclovir 900 mg/12 h until two negative viral loads were detected.

CMV infection was considered as the detection of an increased viral load and/or the presence of CMV in histological samples, regardless of clinical symptoms [7].

Two protocol biopsies were performed after HTx before discharge, followed by monthly medical evaluations and biopsy during the first six months, and at months nine and 12. CMV viral load determinations were included in all follow-up assessments.

Rejection was considered as any event leading to a significant increase in immunosuppressive medication. Infection was considered as any compatible clinical condition requiring hospitalization or prolongation of a hospital stay.

Coronary angiography and intravascular ultrasound (IVUS) assessments were performed at one month and one yr after HTx to detect the presence of cardiac allograft vasculopathy (CAV). Considering CAV as a generalized and diffuse disease, IVUS was performed in the anterior descending artery to assess intimal proliferation. Significant CAV was considered as the presence at any point of intimal proliferation > 1 mm and/or 0.5 mm in 180º [17, 18] in the IVUS at one yr after HTx.

CMV infection, cardiovascular mortality, CAV, primary graft failure, and number of rejections and infections with other microorganisms were analyzed.

Statistical analysis was performed on an intent-to-treat basis. Continuous variables were expressed as mean ± standard deviation and discrete variables as percentages. Student's t-test was used for the analysis of continuous variables, and the chi-square or Fisher's exact test for discrete variables. A multivariate analysis was performed where the dependent variable was CMV infection and the independent variables were those found to be significant in the univariate analysis and indicated in other articles as predisposing for CMV infection [10, 19]. Event-free survival was calculated by the Kaplan-Meier method, and curves were compared with the log-rank test. The statistical package used was SPSS 13.0© (SPSS Inc., Chicago, IL, USA).


  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Authors' contributions
  8. References

Mean age was 52 yr, 73.7% were men, and mean follow-up time was 711.7 ± 408.9 d. The remaining baseline characteristics of both groups are shown in Table 1, although no significant differences were observed between both groups. There was not cross-over between both treatments. Two patients discontinued treatment with Tac because of the appearance of tumors and two patients discontinued treatment with CsA, in one case the patient had a tumor and another patient had CAV. No patients required thymoglobulin or OKT-3.

Table 1. Baseline characteristics of patients studied
 Cyclosporine (n = 51)Tacrolimus (n = 44)p
  1. IDCM, idiopathic dilated cardiomyopathy; BMI, body mass index; HTx, heart transplantation; ICU, intensive care unit; ECMO, extracorporeal membrane oxygenation.

Age (yr)52 ± 1152 ± 120.74
Male (%)72.45750.79
Etiology (%)
BMI25.8 ± 4.225.5 = 3.90.77
Hypertension (%)29.429.50.99
Diabetes mellitus (%)2525.60.95
Dyslipidemia (%)
Smoker (%)
Creatinine (mg/dL)1.13 ± 0.531.06 ± 0.370.49
Albumin levels (d/dL)3.7 ± 0.54.8 ± 3.40.35
Urgent HTx (%)27.543.20.11
ECMO (%)15.722.70.38
Age (yr)40 ± 1239 ± 110.78
Male (%)61.464.70.74
BMI25.2 ± 3.725.4 ± 3.80.81
Surgical procedure
Ischemia time (min)163 ± 53156 ± 490.52
Intubation (h)81 ± 22572 ± 1390.83
ICU line (d)7.3 ± 11.48.5 ± 9.90.59
Blood transfusions (unit)8.1 ± 10.110.7 ± 10.90.59

CMV infection was detected in 31.6% of patients. Of these, 66.7% had asymptomatic CMV replication requiring preemptive therapy, 26.6% developed systemic CMV disease (two patients from this group had received preemptive therapy due to detection of elevated viral load), and 13.3% had local disease.

The rate of CMV infection was higher in patients treated with CsA than in those treated with Tac (45.1% vs. 15.9%, p = 0.002), with no differences being observed in prophylaxis rates between both groups and with a higher percentage of high-risk patients (D+/R−) in the Tac group (Table 2). Event-free survival curves were constructed (Fig. 1). The group of patients treated with CsA had a shorter mean survival time free from CMV infection than patients treated with Tac (900 vs. 1440 d, p = 0.001).

Table 2. Characteristics of infection and CMV prophylaxis
 Cyclosporine (n = 51)Tacrolimus (n = 44)p
  1. D+, IgG-CMV-positive donors; R+, IgG-CMV-posilive recipient; R−, IgG-CMV-negative recipient; D−, IgG-CMV-negative donor WBC; white blood cells.

D+, n (%)36 (70.6)34 (79.1)0.35
- CMV infection, n (%)17 (47.2)7 (20.6)0.019
R+, n (%)44 (83.3)34 (77.3)0.25
- CMV infection, n (%)21 (47.7)4 (11. 8)0.001
D+/R+ (55 patients), n (%)31 (60.8)24 (55.8)0.63
- CMV infection, n (%)15 (48.4)4 (16.7)0.014
D+/R− (15 patients), n (%)5 (9.8)10 (23.3)0.07
- CMV infection, n (%)2 (40)3 (30)1
D−/R+ (23 patients), n (%)13 (25.5)10 (22.7)0.75
- CMV infection, n (%)6 (46.2)00.046
D−/R− (2 patients), n (%)2 (3.9)00.5
- CMV infection, n (%)00 
Prophylaxis, n (%)5 (9.8)10 (22.7)0.085
CMV infection, n (%)23 (45.1)7 (15.9)0.002
Preemptive therapy15 (29.4)5(11.4)0.031
Systemic disease7(13.7)1 (2.3)0.13
Local disease2 (3.9)2 (4.5) 
CMV infection-free survival (days)899.9 ± 102.51440.1 ± 75.)0.001
Mean serum levels of drug (ng/mL)
< 6 months290.5 ± 56.412.1 ± 4.1 
> 6 months204.5 ± 59.710.5 ±  4.0 
Highest level of drug (ng/mL)372.6 ± 113.217.3 ± 4.7 
VVBC prior infection (109/L)6.52 ± 3.055.35 ± 1.540.46

Figure 1. Kaplan–Meier curve of CMV infection.

Download figure to PowerPoint

Analyzing infection by risk groups, the group with the highest risk of CMV infection (D+/R−) maintained a non-significant trend to present more infection in patients treated with CsA opposite to Tac, although the number of patients with CMV infection in this group was very small (two patients of 5–40% in the CsA group and three patients of 10–30% in the Tac group). In the group of patients with IgG-CMV-positive recipients (D+/R+ and D−/R+), the rate of CMV infection was similar to that of the high-risk group (D+/R−) (32.5% and 33.3%, respectively, p = 0.95). So, analyzing the rate of CMV infection according to the CNI used in the group IgG-CMV-positive recipients, it was also significantly higher in the CsA group (47.7 vs. 11.8%, p = 0.001).

No differences were observed in cardiovascular mortality between both study groups (5.9% in the CsA group vs. 15.9% in the Tac group, p = 0.12), in the incidence of CAV (36.4% vs. 44.1%, respectively, p = 0.49), or in mean survival (689.9 ± 375.9 d and 749.9 ± 446.2 d, respectively, p = 0.48).

Other viral infections were mostly by herpes simplex virus, and there was one case of varicella. Regarding other non-viral infections, there were no significant differences between both study groups, as shown in Table 3.

Table 3. Post-transplant complications
 Cyclosporine (n = 51)Tacrolimus (n = 44)p
  1. PSI, proliferation signal inhibitors.

Cardiovascular mortality, n (%)3 (5.9)7 (15.9)0.18
Primary graft failure, n (%)12(23.5)8 (18.2)0.52
Rejection, n (%)32 (66.7)27 (61.4)0.6
Number of rejections1 ± 0.920.93 ± 0.920.72
Cardiac allograft vasculopathy, n (%)16 (36.4)15 (44.1)0.49
Non-CMV viral infections, n (%)12 (24)3 (6.8)0.02
Bacterial infections, n (%)9 (17.6)14 (31.8)0.11
Fungal infections, n (%)1 (2)5 (11.4)0.09
Unknown infections, n (%)2 (3.9)5 (11.4)0.24
Treatment with PSI, n (%)10 (19.6)9 (20.5)0.92

A multivariate analysis was performed to detect which variables could be involved in the development of CMV infection. The variables included in this analysis were those significant in the univariate analysis, together with those which, according to other articles, were predisposing for CMV infection [10, 19] (Table 4). After this analysis, we identified treatment with CsA and bacterial infections as independent risk factors. However, renal function, CMV prophylaxis, age of donor and recipient, primary graft failure, the number of rejections, or serostatus were not predisposing factors.

Table 4. Univariate and multivariate analysis for CMV infection
  1. D+, IgG-CMV-positive donors; R+, IgG-CMV-positive recipient; R−, IgG-CMV-negative recipient; ECMO, extracorporeal membrane oxygenation; BMI, body mass index.

Cyclosporine4.340.002(1.63–11.55)9.53< 0.001(2.69–33.77)
CMV prophylaxis1.11(0.34–3.56)0.750.67(0.19–2.92)
No. of rejections1.120.63(0.7–1.8)1.050.87(0.19–2.92)
Induction therapy basiliximab0.730.58(0.24–2.25)   
Primary graft failure2.10.15(0.76–5.81)   
Ischemia time1.010.06(0.99–1.02)   
Donor age0.990.69(0.96–1.03)0.980.36(0.94–1.02)
Recipient age1.030.25(0.98–1.07)   
Previous creatinine0.960.93(0.37–2.48)   
Creatinine at one yr0.770.72(0.18–3.32)   
Bacterial infections2.560.05(0.97–6.76)5.880.007(1.6–21.47)
Blood transfusions0.970.5(0.91–1.1)   
Albumin levels0.990.99(0.47–2.12)   


  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Authors' contributions
  8. References

Our study is the first randomized study comparing the rate of CMV infection in heart transplant patients treated with CsA or Tac within a standard immunosuppressive regimen, finding a lower rate of CMV infection in patients treated with Tac.

CMV infection is of one of the most common infectious complications in solid organ transplant patients [3, 7, 20]. The highest risk of developing CMV infection after HTx is when there is a serological mismatch between donor and recipient, with the highest risk for the D+/R− group.

The most common immunosuppressive therapy in HTx patients is based on a CNI, MMF, and steroids. Numerous studies have been conducted to compare both CNIs (CsA and Tac) in HTx, reaching the general conclusion that CsA promotes dyslipidemia, arterial hypertension, and hypertricosis, whereas Tac is somewhat more potent, with a lower rate of acute rejection, but causes more diabetes and a higher incidence of gastrointestinal symptoms in combination with MMF [16, 21, 22]. Although both have a similar mechanism of action, each drug binds to distinct cytosolic proteins. CsA binds to cyclophilins and Tac binds to FK-binding protein with greater binding affinity than CsA. In vitro and in vivo studies have shown that CsA and Tac have a different effect on various factors, such as synthesis of IL-10, which could explain the differences between both drugs in efficacy and immunosuppressive activity [23-25]. This different action may explain that the incidence of CMV infection was higher in the CsA group. With respect to the rate of infection, in comparative studies between both drugs in HTx patients, no significant differences were observed in the overall infection rate [26-28] or in CMV infection rate [29]. It has only been published that there is a higher trend to viral infections with CsA than with Tac [16], but to date no studies have been conducted with the objective of comparing the rate of CMV infection in both treatment groups.

As observed in the results section, the overall rate of CMV infection in our patients was 31.6%, similar to that reported in other published studies [10, 30], although the rate of CMV disease (12.6%) was lower than that reported in these studies. According to the results, the patients in this study developed infection in the same proportion as other HTx patients, but it progressed to disease in fewer cases. We attribute this difference to the fact that, although we follow the same immunosuppressive regimen than in most HTx centers, CNI target levels are clearly lower [16, 29, 31, 32] in our center, so patients have a lower immunosuppressive load. This together with the prophylaxis administered in the high-risk group and the routine detection of viral load by PCR (more sensitive and reproducible than other determinations) at each medical evaluation would allow us to detect infection early and start preemptive therapy to prevent the development of CMV disease.

Regarding the CMV infection rate, we observed that 45.1% of patients treated with CsA had at least one CMV infection compared to 15.9% of patients treated with Tac. CMV infection-free survival time was lower in the group treated with CsA than in those treated with Tac (900 vs. 1440 d). To date, similar results with CsA and Tac have been only reported in kidney transplants [19], but never in HTx. Our group already documented a higher rate of viral infections with CsA vs. Tac, but without focusing on the etiology of these infections [16]. These results were obtained despite the fact that the percentage of high-risk patients (D+/R−) was higher in the group of patients treated with Tac (23.3%) than in the group with CsA (9.8%). It is universally accepted that the most important predictor of risk of developing CMV infection is due to the risk of infection through the transplanted organ. On the other hand, the delay in the development of an infection in both groups can be explained by a delayed start of CMV replication after completing prophylactic treatment [33, 34]. Due to greater number of high-risk patients in the Tac group, the percentage of the prophylaxis is also higher in this group. But patients with more risk of infection have been treated with prophylaxis in both groups, so this should not affect in that the CMV infection is fewer in Tac group. Moreover, differences in the rates of CMV infection are remained in the other groups, therefore the percentage of patients with D+/R− status is not the main group that makes this difference exists.

In addition, recipients with positive serology (D+/R+ and D−/R+) may comprise a group at risk of infection due to reactivation of latent virus. In fact, in our study the percentage of patients with CMV infection in this group was similar to the high-risk group (D+/R−) (32.5% and 33.3%, respectively). In previous studies [10, 14] on CMV infection, infection rates in the group of patients with R+ serology are not indicated, so these data could not be compared with the results of other groups. In this subgroup of patients, the differences in CMV infection rate are remained depending on the CNI used (47.7% with CsA vs. 11.8% with Tac).

There were no significant differences in mortality or in the number of rejections between the group treated with CsA or with Tac, although previous studies had obtained lower rejection rates in the group treated with Tac [16, 21]. Similar results have already been published by Kobashigawa et al. [35] in a comparative study Tac vs. CsA, in which there were not differences in the rates of freedom from rejection between both groups. There was neither a difference in the incidence of CAV observed between both drugs (36.4% vs. 44.1%), data that had been published by our group [36] and that coincide with those published by other authors [28]. In our series, the incidence of CAV at one yr after HTx was 39.7%. However, the incidence of CAV at one yr according to the data in the 2010 ISHLT registry [37] is 8%. This difference could be explained by the different methods for diagnosing CAV [38]. In our series, IVUS was used as the diagnostic technique, whereas in the ISHLT Registry, diagnosis was done by coronary angiography, which was a less sensitive method for the diagnosis of CAV in early stages of the disease. Thus, the incidence of CAV in our study agrees with that shown in other studies using IVUS for the diagnosis of CAV, where the incidence ranges from 19% to 45% [17, 18].

In our study we did not find a relationship between CMV infection and other factors reported in the literature such as donor and recipient serology, donor and recipient age, renal dysfunction, or induction therapy [18, 19]. Only treatment with CsA and presence of bacterial infections were independent risk factors for CMV infection. This might be explained by the immunosuppressive state of these patients, which promotes the development of infections by various microorganisms, therefore, patients who have either a viral or bacterial infection are probably more susceptible to suffer another type of infection.

Over the last few years, there has been a trend to a decreased use of CsA in favor of Tac. In fact, according to the 2011 ISHLT analysis, Tac has surpassed CsA as the most used CNI (73% vs. 20%) in HTx [39]. This might be due to the results obtained in comparative studies of both drugs, where it was seen that Tac decreased rejection rates compared with CsA, although these results were not accompanied by an increase in survival. In our study we also observed that patients receiving treatment with Tac had a lower rate of CMV infection. As CMV infection was associated with higher rates of rejection, renal failure, and CAV, preventing CMV was beneficial to reduce morbidity in HTx. For this reason, we think it is interesting to know which immunosuppressive therapy is associated with a lower rate of CMV infection, as its use could lead to lower morbidity and mortality in heart transplant patients. In view of these results, the switch from CsA to Tac could be recommended in those patients who have developed CMV infection.

A limitation of the study is the relatively low number of patients included. However, the fact that it was a randomized single center study confers much reliability to the results and ensures an identical protocol in all patients. On the other hand, in our protocol, routine screening for CAV was not performed after one yr from HTx, and only coronary angiography guided by symptoms or when graft dysfunction was detected in the follow-up, so the rates of CAV were probably higher.

This study was the first to demonstrate a lower rate of CMV infection in patients treated with Tac vs. those treated with CsA within a standard immunosuppressive regimen after HTx. Tacrolimus may reduce the possibility of developing CMV infection and it may as well delay its occurrence.

In view of the results, we consider it is justified to use tacrolimus instead to cyclosporine in those patients at higher risk of developing CMV infection and those in which this infection is difficult to manage.


  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Authors' contributions
  8. References

This work was been translated with a no-conditions grant from Roche Pharma. Our thanks to Mónica Cebrián for her collaboration.

Authors' contributions

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Authors' contributions
  8. References

M. Rodríguez-Serrano analyzed and interpreted the data and wrote the article. I. Sánchez-Lázaro conceived and designed the study. He analyzed and interpreted the data and wrote the article. L. Almenar Bonet conceived and designed the study. He critically reviewed and approved the article. L. Martínez-Dolz, M. Portolés Sanz, M. Rivera Otero, and A. Salvador Sanz critically reviewed and approved the article. All authors have agreed to submission of the article in its present form.


  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Authors' contributions
  8. References
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