Induction immunosuppression after heart transplantation: monoclonal vs. polyclonal antithymoglobulins. Is there a difference
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《血管的通路杂志》
a Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, K1Y-4W7, Canada
b Department of Epidemiology, University of Ottawa, Ottawa, K1Y-4W7, Canada
Abstract
Induction immunosuppression after heart transplantation is believed to reduce the risk of acute graft rejection. While monoclonal and polyclonal antithymoglobulins are considered the optimal induction agents, controversy remains regarding their relative superiority. This article presents a systematic review of the literature and a meta-analysis in order to assess the relative benefits and side-effects of monoclonal vs. polyclonal antithymoglobulins as induction immunosuppression agents. Pooled analysis demonstrated a small but statistically insignificant difference in the average time to first rejection between the groups (6.7±15.5 days, P=0.39). No statistically significant differences in the proportion of patients who developed rejection or infection episodes at 6 months were observed (Relative Risk 0.97, P=0.82 and Relative Risk 0.85, P=0.14, respectively). In addition, no statistically significant difference in survival was found between the groups at 6 months (Relative Risk 0.98, P=0.58). A greater number of drug related side-effects was observed, however, in the monoclonal group, including episodes of acute pulmonary edema and hypotension. In conclusion, this review revealed no statistically significant differences in rejection, infection, or survival rates between the monoclonal and polyclonal groups. The increased rate of side-effects with monoclonal antibodies might suggest a superiority of polyclonal over monoclonal antibodies.
Key Words: Heart transplantation; Immunosuppression; Monoclonal; Polyclonal; Thymoglobulin
1. Introduction
The long-term results of cardiac transplantation have continued to improve due to improved peri-operative care and immunosuppression regimens. The risk for acute rejection is highest in the first year following transplantation and therefore many transplant centers use a strategy of peri-operative induction immunosuppression in order to provide a rapid and effective protection against acute allograft rejection [1,2]. Reducing the number of T-cells, which are responsible for graft rejection, is believed to be the most effective method to achieve a rapid and effective immunosuppression early post-transplantation. Two main types of antithymoglobulin preparations are currently available, namely polyclonal and monoclonal antibodies. The superiority of either agent continues to be unresolved [3–13]. The purpose of this study therefore was to systematically review all available trials that compared the benefits and harms of polyclonal and monoclonal antithymoglobulins when used as induction immunosuppression agents after heart transplantation.
2. Materials and methods
A systematic review of the literature was conducted to identify all randomized controlled trials that compared polyclonal and monoclonal antithymoglobulins as induction immunosuppression agents after heart transplantation. The search was conducted using the electronic data-bases Pre-MEDLINE, MEDLINE (1966 to March 2004), EMBASE (1980 to March 2004), and the Cochrane Central Register of Controlled Trials (2004). Studies that included any of the following MeSH or text words were identified: ‘monoclonal antibodies’, ‘polyclonal antibodies’, ‘OKT3’, ‘Orthoclone’, ‘ATG’, ‘ALG’, ‘Thymoglobulin’, ‘Rabbit Anti-Thymo-globulin’, ‘RATG’, ‘Horse Anti-Thymoglobulin’, or ‘HATG’. All identified studies were then combined with the term ‘HEART’. The search was then restricted to randomized-controlled trials using the Dickersin filter [14]. The references of all identified articles were also searched. Trials involving non-human or pediatric subjects (<18 years) were excluded. No restriction based on language or country of publication was imposed. No attempts were made to identify unpublished or non-peer reviewed articles. All studies were screened by two reviewers (MH and FA).
The quality of all relevant trials was assessed using the Jadad scale [15]. Studies that scored 3 out of 5 were considered high quality. The primary outcomes of interest included the number of patients who developed acute rejection episodes in the first 6 months post-transplantation, the incidence of post-operative infections, survival, and drug related side-effects. Clinically important rejection was defined as episodes requiring treatment (rejection grade 2 out of 4 using the International Society of Heart and Lung Transplantation Scale). Post-operative infections were defined as episodes requiring treatment. An attempt was made to obtain any missing information from the primary authors.
2.1. Data analysis
All eligible studies were included in the analysis regardless of quality or the blinding status. The computer software RevMan (Version 4.2, Cochrane Collaboration) was used. The weighted difference of means with 95% confidence intervals was used for continuous variables and pooled relative risk estimates with 95% confidence intervals were used for dichotomous variables. Estimates of rejection, infection, and survival rates were calculated at 6 months post-transplantation. The conservative random effects model was used for our analysis. A pooled relative risk of 1 indicates no difference between the groups whereas a relative risk of <1 indicates a lower risk of events in the polyclonal group compared to the monoclonal group. Medication related side-effects were summarized in a table format since the data could not be pooled. Test of heterogeneity between the studies was conducted using the chi-square method and sensitivity analysis of high and low quality studies was also planned.
3. Results
A total of 1309 articles were identified by our literature search strategy. Of those, only 11 articles compared polyclonal and monoclonal antithymoglobulins in adult heart transplant patients and, therefore, deemed potentially eligible for inclusion [3–13]. However, only 5 trials were truly randomized and were therefore included in the final analysis [4,6–9]. Only one trial stated that the pathologist was blinded to treatment groups and one trial utilized concealed envelopes for randomization [4,6]. All included studies were published in English. Table 1 displays the characteristics of the 5 included trials. The studies enrolled a total of 105 polyclonal patients (ATG group) and 110 monoclonal patients (OKT3 group). Following induction of immunosuppression, all patients received steroids and cyclosporine in addition to azathyprine in selected patients. ATG and OKT3 doses were similar in the various studies but there was a discrepancy in the duration of drug administration. Four trials used ATG for 7 days compared to 14 days in the OKT3 group and one trial used both ATG and OKT3 for an equal length of time [8]. Follow-up ranged from 6 to 24 months post-transplantation. The methods of data reporting varied among the studies rendering pooling of some results difficult. Furthermore, measures of spread, such as standard deviations, were not consistently reported. Only one trial scored 3 out of 5 on the Jadad scale, while the remaining trials scored only 2 out of 5 due to the lack of blinding.
3.1. Rejection
3.1.1. Time to first rejection episode
Fig. 1 demonstrates a statistically insignificant delay in the mean time to first rejection episode in the ATG group compared to the OKT3 group (average difference of 6.7 days, 95% confidence interval –9 to +22 days, P=0.39). The heterogeneity test between the studies was significant (P<0.00001).
3.1.2. Number of patients with rejection episodes
Three trials reported the average number of rejection episodes per patient as well as the number of patients who developed rejection [6–8] while one trial only reported the average number of rejection episodes per patient [4], and one trial did not report any data [9]. Fig. 2A demonstrates that there was no difference in the risk of graft rejection between the two groups at 6 months post-transplantation (relative risk 0.97, confidence interval 0.72–1.3). Two studies, however, could not be included in the pooled analysis due to the method of data reporting. One of those trials demonstrated a higher incidence of rejection in the ATG group [4] while the other study showed that there was no difference between the groups at 6 months [9].
3.2. Infections
The pooled effect estimate demonstrated a trend towards a lower proportion of patients with post-operative infections at 6 months in the ATG group (relative risk 0.85, confidence interval 0.69–1.05), however, this trend did not reach statistical significance (P=0.14) (Fig. 2B). One study could not be included in the pooled analysis due to the lack of data [7]. That study, however, also showed a slightly lower number of infection episodes per patient in the ATG group, albeit this difference was not statistically significant.
3.3. Survival
The pooled relative risk for survival up to 1 year between the groups was 0.98 with a 95% confidence interval of 0.91–1.06, P=0.58 (Fig. 2C). One study, however, could not be included due to lack of survival data beyond 3 months [4].
3.4. Side effects
Table 2 summarizes the rates of all medication related side-effects. Most studies reported higher rates of drug related complications in the OKT3 group. These side-effects included fever, headaches, acute respiratory distress, and hypotension.
4. Discussion
Various studies have demonstrated the effectiveness of peri-operative antithymoglobulins in reducing the risk of acute graft rejection after heart transplantation [1,2]. In addition, induction with these agents allows for the stabilization of renal function by delaying the need for the nephrotoxic calcinurine inhibitors. Controversy remains, however, regarding the relative advantages of polyclonal compared to monoclonal thymoglobulins. This systematic review demonstrated that while there was a slight delay in the average time to first rejection in the ATG group, this difference was statistically and clinically insignificant. Furthermore, the proportion of patients who experienced a rejection episode in the first 6 months was similar in both groups. Unfortunately, two trials could not be included in the pooled estimate due to the variability in data reporting. This was due to the fact that 3 studies reported the number of patients with events at various points in time, while the rest reported the average number of events per patient. While some non-randomized clinical trials also demonstrated a trend towards lower rejection episodes in ATG patients [3,10,12] others, however, demonstrated a superiority of OKT3 over ATG [5]. This meta-analysis only analyzed randomized controlled trials in order to minimize the risk of selection and information bias and reduce the effects of possible confounders.
The number of post-operative infections requiring treatment was slightly lower in ATG patients but this difference did not reach statistical significance. Furthermore, most infections were successfully treated without major sequelae. The similar rate of post-operative infections between the ATG and OKT3 groups is reassuring. However, many studies have demonstrated a relatively high incidence of side-effects after the initial OKT3 dose [3,6]. Most of these complications were transient with minimal long term sequelae but few patients sustained major side-effects such as respiratory and hemodynamic decompensation. These complications occurred despite pre-treatment with steroids and anti-histamines. Hence, close monitoring is currently recommended in all patients receiving OKT3. ATG related side-effects were infrequent, however, some studies reported a slight risk of thrombocytopenia and leukopenia and therefore platelet and white cell counts should be monitored closely in those patients. The cost of ATG is, however, greater than monoclonal anti-thymoglobulins. The cost of a 5-day course of ATG is approximately CAN $ 7500 (5 vials/day) compared to CAN $ 3200 of OKT3 (5 mg/day).
There was no survival difference between the two groups up to 1 year post-transplantation. This could be due to the fact that the two major influences on survival, namely rejection and infection episodes, were similar in both groups. Furthermore, no major differences in the incidence of lymphomas were observed between ATG and OKT3 patients in this review.
The systematic nature of this review ensures the inclusion of all relevant trials. In addition, limiting the analysis to randomized controlled trials only strengthens the conclusions of this review.
A weakness of this meta-analysis lies in the fact that some studies could not be pooled for certain end-points, such as drug related side-effects. It was difficult to pool the results of all trials due to discrepancies in the methods of data reporting. However, most trials were included in the pooled estimates of the major outcomes. Another weakness in the meta-analysis is the fact that different doses and time intervals were utilized in the different trials. This would weaken the strength of the quantitative portion of this review. All included studies had equivalent quality scores and therefore no sensitivity analysis for this variable was necessary. Only one study was deemed to be of high quality since 4 of the 5 trials were not blinded. It could be argued, however, that blinding of clinicians and patients should not affect the end points of the studies, namely histologic rejection grade, infections, and survival. Blinding, however, could have been achieved in these trials.
The risk of publication bias threatens the validity of many systematic reviews. Such bias occurs due to the fact that negative trials are less likely to be published than positive ones. Most trials in this review reported negative results and therefore the risk of a publication bias was not of a major concern.
In conclusion, a systematic search of the literature did not reveal any statistically or clinically significant differences in the rates of rejection or infection episodes between patients receiving monoclonal and polyclonal antithymoglobulins as induction immunosuppression agents after cardiac transplantation. Furthermore, no differences in survival rates were observed up to 1 year post-transplantation. However, a higher incidence of drug related side-effects was found in the monoclonal group. Caution should be exercised after the initial dose of monoclonal antithymoglobulins due to the small risk of respiratory and hemodynamic compromise. The results of this review underscore the importance of conducting a large, multi-centered, randomized clinical trial to address this issue.
References
Kormos RL, Armitage JM, Dummer JS, Miyamoto Y, Griffith BP, Hardesty RL. Optimal perioperative immunosuppression in cardiac transplantation using rabbit antithymocyte globulin. Transplantation 1990;49:306–311.
Kobashigawa JA, Stevenson LW, Brownfield E, Moriguchi JD, Kawata N, Hamilton M, Minkely R, Drinkwater D, Laks H. Does short-course induction with OKT3 improve outcome after heart transplantation A randomized trial. J Heart Lung Transplant 1993;12:250–258.
Kormos RL, Herlan DB, Armitage JM, Stein K, Kaufman C, Zeevi A, Duquesnoy R, Herdesty RL, Griffith BP. Monoclonal versus polyclonal antibody therapy for prophylaxis against rejection after heart transplantation. J Heart Lung Transplant 1990;9:1–10.
Costanzo-Nordin MR, O'Sullivan EJ, Johnson MR, Winters GL, Pifarre R, Radvany R, Zucker MJ, Scanlon PJ, Robinson JA. Prospective randomized trial of OKT3 vs. horse antithymocyte globulin-based immuno-suppressive prophylaxis in heart transplantation. J Heart Transplantation 1992;9:306–315.
Renlund DG, O'Connell JB, Gilbert EM, Hammond ME, Burton NA, Jones KW, Karwande SV, Doty DB, Menlove RL, Herrick CM, Lee HR, Gay WA, Bristow MR. A prospective comparison of murine monoclonal CD-3 (OKT3) antibody-based and equine antithymocyte globulin-based rejection prophylaxis in cardiac transplantation. Decreased rejection and less corticosteroid use with OKT3. Transplantation 1989;47:599–605.
Griffith BP, Kormos RL, Armitage JM, Dummer JS, Hardesty RL. Comparative trial of immunoprophylaxis with RATG vs. OKT3. J Heart Transplant 1990;9:301–305.
MacDonald PS, Mundy J, Keogh AM, Chang VP, Spratt PM. A prospective randomized study of prophylactic OKT3 vs. equine antithymocyte globulin after heart transplantation increased morbidity with OKT3. Transplantation 1993;55:110–116.
Menkis AH, Powell AM, Novick RJ, McKenzie FN, Kostuk WJ, Pflugfelder PW, Brown JE, Rochon J, Chow LH, Stiller C. A prospective randomized controlled trial of initial immunosuppression with ALG vs. OKT3 in recipients of cardiac allografts. J Heart Lung Transplantation 1992;11:569–576.
Ippoliti G, Negri M, Abelli P, Rovati B, Di Franco L, Grossi P, Minoli L, Ascari E, Vigano M. Preoperative prophylactic OKT3 vs. RATG. A randomized clinical study in heart transplantation. Transplantation Proceedings 1991;23:2272–2274.
Laske A, Gallino A, Schneider J, Bauer EP, Carrel T, Pasic M, Von Segesser LK, Turina MI. Prophylactic cytolytic therapy in heart transplantation: Monoclonal vs. polyclonal antibody therapy. J Heart Lung Transplantation 1992;11:557–563.
Kirklin JK, Bourge RC, White-Williams C, Naftel DC, Thomas FT, Thomas JM, Phillips MG. Prophylactic therapy for rejection after cardiac transplantation: a comparison of rabbit antithymocyte globulin and OKT3. J Thorac Cardiovasc Surg 1990;99:716–724.
Ladowski JS, Dollon T, Schatzlein MH, Peterson AC, Deschner WP, Beatty L, Sullivan M, Scheeringa RH, Clark WR. Prophylaxis of heart transplant rejection with either antithymocyte globulin-Minnesota antilymphocyte globulin-, or an OKT3-based protocol. J Cardiovasc Surg (Torino) 1993;34:135–140.
Balk AH, Meeter K, Simoons ML, Brouwer RM, Zondervan PE, Mochtar B, Bos E, Weimar W. Polyclonal vs. monoclonal rejection prophylaxis after heart transplantation: a randomized study. Transplant International 1992;5:S476–S479.
Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. Brit Med J 1994;309:1286–1291.
Jadad AR, Moore RA, Carrol D. Assessing the quality of reports of randomized clinical trials: is blinding necessary. Control Clin Trials 1996;17:1–12.(Michel Haddad, Fahad S. A)
b Department of Epidemiology, University of Ottawa, Ottawa, K1Y-4W7, Canada
Abstract
Induction immunosuppression after heart transplantation is believed to reduce the risk of acute graft rejection. While monoclonal and polyclonal antithymoglobulins are considered the optimal induction agents, controversy remains regarding their relative superiority. This article presents a systematic review of the literature and a meta-analysis in order to assess the relative benefits and side-effects of monoclonal vs. polyclonal antithymoglobulins as induction immunosuppression agents. Pooled analysis demonstrated a small but statistically insignificant difference in the average time to first rejection between the groups (6.7±15.5 days, P=0.39). No statistically significant differences in the proportion of patients who developed rejection or infection episodes at 6 months were observed (Relative Risk 0.97, P=0.82 and Relative Risk 0.85, P=0.14, respectively). In addition, no statistically significant difference in survival was found between the groups at 6 months (Relative Risk 0.98, P=0.58). A greater number of drug related side-effects was observed, however, in the monoclonal group, including episodes of acute pulmonary edema and hypotension. In conclusion, this review revealed no statistically significant differences in rejection, infection, or survival rates between the monoclonal and polyclonal groups. The increased rate of side-effects with monoclonal antibodies might suggest a superiority of polyclonal over monoclonal antibodies.
Key Words: Heart transplantation; Immunosuppression; Monoclonal; Polyclonal; Thymoglobulin
1. Introduction
The long-term results of cardiac transplantation have continued to improve due to improved peri-operative care and immunosuppression regimens. The risk for acute rejection is highest in the first year following transplantation and therefore many transplant centers use a strategy of peri-operative induction immunosuppression in order to provide a rapid and effective protection against acute allograft rejection [1,2]. Reducing the number of T-cells, which are responsible for graft rejection, is believed to be the most effective method to achieve a rapid and effective immunosuppression early post-transplantation. Two main types of antithymoglobulin preparations are currently available, namely polyclonal and monoclonal antibodies. The superiority of either agent continues to be unresolved [3–13]. The purpose of this study therefore was to systematically review all available trials that compared the benefits and harms of polyclonal and monoclonal antithymoglobulins when used as induction immunosuppression agents after heart transplantation.
2. Materials and methods
A systematic review of the literature was conducted to identify all randomized controlled trials that compared polyclonal and monoclonal antithymoglobulins as induction immunosuppression agents after heart transplantation. The search was conducted using the electronic data-bases Pre-MEDLINE, MEDLINE (1966 to March 2004), EMBASE (1980 to March 2004), and the Cochrane Central Register of Controlled Trials (2004). Studies that included any of the following MeSH or text words were identified: ‘monoclonal antibodies’, ‘polyclonal antibodies’, ‘OKT3’, ‘Orthoclone’, ‘ATG’, ‘ALG’, ‘Thymoglobulin’, ‘Rabbit Anti-Thymo-globulin’, ‘RATG’, ‘Horse Anti-Thymoglobulin’, or ‘HATG’. All identified studies were then combined with the term ‘HEART’. The search was then restricted to randomized-controlled trials using the Dickersin filter [14]. The references of all identified articles were also searched. Trials involving non-human or pediatric subjects (<18 years) were excluded. No restriction based on language or country of publication was imposed. No attempts were made to identify unpublished or non-peer reviewed articles. All studies were screened by two reviewers (MH and FA).
The quality of all relevant trials was assessed using the Jadad scale [15]. Studies that scored 3 out of 5 were considered high quality. The primary outcomes of interest included the number of patients who developed acute rejection episodes in the first 6 months post-transplantation, the incidence of post-operative infections, survival, and drug related side-effects. Clinically important rejection was defined as episodes requiring treatment (rejection grade 2 out of 4 using the International Society of Heart and Lung Transplantation Scale). Post-operative infections were defined as episodes requiring treatment. An attempt was made to obtain any missing information from the primary authors.
2.1. Data analysis
All eligible studies were included in the analysis regardless of quality or the blinding status. The computer software RevMan (Version 4.2, Cochrane Collaboration) was used. The weighted difference of means with 95% confidence intervals was used for continuous variables and pooled relative risk estimates with 95% confidence intervals were used for dichotomous variables. Estimates of rejection, infection, and survival rates were calculated at 6 months post-transplantation. The conservative random effects model was used for our analysis. A pooled relative risk of 1 indicates no difference between the groups whereas a relative risk of <1 indicates a lower risk of events in the polyclonal group compared to the monoclonal group. Medication related side-effects were summarized in a table format since the data could not be pooled. Test of heterogeneity between the studies was conducted using the chi-square method and sensitivity analysis of high and low quality studies was also planned.
3. Results
A total of 1309 articles were identified by our literature search strategy. Of those, only 11 articles compared polyclonal and monoclonal antithymoglobulins in adult heart transplant patients and, therefore, deemed potentially eligible for inclusion [3–13]. However, only 5 trials were truly randomized and were therefore included in the final analysis [4,6–9]. Only one trial stated that the pathologist was blinded to treatment groups and one trial utilized concealed envelopes for randomization [4,6]. All included studies were published in English. Table 1 displays the characteristics of the 5 included trials. The studies enrolled a total of 105 polyclonal patients (ATG group) and 110 monoclonal patients (OKT3 group). Following induction of immunosuppression, all patients received steroids and cyclosporine in addition to azathyprine in selected patients. ATG and OKT3 doses were similar in the various studies but there was a discrepancy in the duration of drug administration. Four trials used ATG for 7 days compared to 14 days in the OKT3 group and one trial used both ATG and OKT3 for an equal length of time [8]. Follow-up ranged from 6 to 24 months post-transplantation. The methods of data reporting varied among the studies rendering pooling of some results difficult. Furthermore, measures of spread, such as standard deviations, were not consistently reported. Only one trial scored 3 out of 5 on the Jadad scale, while the remaining trials scored only 2 out of 5 due to the lack of blinding.
3.1. Rejection
3.1.1. Time to first rejection episode
Fig. 1 demonstrates a statistically insignificant delay in the mean time to first rejection episode in the ATG group compared to the OKT3 group (average difference of 6.7 days, 95% confidence interval –9 to +22 days, P=0.39). The heterogeneity test between the studies was significant (P<0.00001).
3.1.2. Number of patients with rejection episodes
Three trials reported the average number of rejection episodes per patient as well as the number of patients who developed rejection [6–8] while one trial only reported the average number of rejection episodes per patient [4], and one trial did not report any data [9]. Fig. 2A demonstrates that there was no difference in the risk of graft rejection between the two groups at 6 months post-transplantation (relative risk 0.97, confidence interval 0.72–1.3). Two studies, however, could not be included in the pooled analysis due to the method of data reporting. One of those trials demonstrated a higher incidence of rejection in the ATG group [4] while the other study showed that there was no difference between the groups at 6 months [9].
3.2. Infections
The pooled effect estimate demonstrated a trend towards a lower proportion of patients with post-operative infections at 6 months in the ATG group (relative risk 0.85, confidence interval 0.69–1.05), however, this trend did not reach statistical significance (P=0.14) (Fig. 2B). One study could not be included in the pooled analysis due to the lack of data [7]. That study, however, also showed a slightly lower number of infection episodes per patient in the ATG group, albeit this difference was not statistically significant.
3.3. Survival
The pooled relative risk for survival up to 1 year between the groups was 0.98 with a 95% confidence interval of 0.91–1.06, P=0.58 (Fig. 2C). One study, however, could not be included due to lack of survival data beyond 3 months [4].
3.4. Side effects
Table 2 summarizes the rates of all medication related side-effects. Most studies reported higher rates of drug related complications in the OKT3 group. These side-effects included fever, headaches, acute respiratory distress, and hypotension.
4. Discussion
Various studies have demonstrated the effectiveness of peri-operative antithymoglobulins in reducing the risk of acute graft rejection after heart transplantation [1,2]. In addition, induction with these agents allows for the stabilization of renal function by delaying the need for the nephrotoxic calcinurine inhibitors. Controversy remains, however, regarding the relative advantages of polyclonal compared to monoclonal thymoglobulins. This systematic review demonstrated that while there was a slight delay in the average time to first rejection in the ATG group, this difference was statistically and clinically insignificant. Furthermore, the proportion of patients who experienced a rejection episode in the first 6 months was similar in both groups. Unfortunately, two trials could not be included in the pooled estimate due to the variability in data reporting. This was due to the fact that 3 studies reported the number of patients with events at various points in time, while the rest reported the average number of events per patient. While some non-randomized clinical trials also demonstrated a trend towards lower rejection episodes in ATG patients [3,10,12] others, however, demonstrated a superiority of OKT3 over ATG [5]. This meta-analysis only analyzed randomized controlled trials in order to minimize the risk of selection and information bias and reduce the effects of possible confounders.
The number of post-operative infections requiring treatment was slightly lower in ATG patients but this difference did not reach statistical significance. Furthermore, most infections were successfully treated without major sequelae. The similar rate of post-operative infections between the ATG and OKT3 groups is reassuring. However, many studies have demonstrated a relatively high incidence of side-effects after the initial OKT3 dose [3,6]. Most of these complications were transient with minimal long term sequelae but few patients sustained major side-effects such as respiratory and hemodynamic decompensation. These complications occurred despite pre-treatment with steroids and anti-histamines. Hence, close monitoring is currently recommended in all patients receiving OKT3. ATG related side-effects were infrequent, however, some studies reported a slight risk of thrombocytopenia and leukopenia and therefore platelet and white cell counts should be monitored closely in those patients. The cost of ATG is, however, greater than monoclonal anti-thymoglobulins. The cost of a 5-day course of ATG is approximately CAN $ 7500 (5 vials/day) compared to CAN $ 3200 of OKT3 (5 mg/day).
There was no survival difference between the two groups up to 1 year post-transplantation. This could be due to the fact that the two major influences on survival, namely rejection and infection episodes, were similar in both groups. Furthermore, no major differences in the incidence of lymphomas were observed between ATG and OKT3 patients in this review.
The systematic nature of this review ensures the inclusion of all relevant trials. In addition, limiting the analysis to randomized controlled trials only strengthens the conclusions of this review.
A weakness of this meta-analysis lies in the fact that some studies could not be pooled for certain end-points, such as drug related side-effects. It was difficult to pool the results of all trials due to discrepancies in the methods of data reporting. However, most trials were included in the pooled estimates of the major outcomes. Another weakness in the meta-analysis is the fact that different doses and time intervals were utilized in the different trials. This would weaken the strength of the quantitative portion of this review. All included studies had equivalent quality scores and therefore no sensitivity analysis for this variable was necessary. Only one study was deemed to be of high quality since 4 of the 5 trials were not blinded. It could be argued, however, that blinding of clinicians and patients should not affect the end points of the studies, namely histologic rejection grade, infections, and survival. Blinding, however, could have been achieved in these trials.
The risk of publication bias threatens the validity of many systematic reviews. Such bias occurs due to the fact that negative trials are less likely to be published than positive ones. Most trials in this review reported negative results and therefore the risk of a publication bias was not of a major concern.
In conclusion, a systematic search of the literature did not reveal any statistically or clinically significant differences in the rates of rejection or infection episodes between patients receiving monoclonal and polyclonal antithymoglobulins as induction immunosuppression agents after cardiac transplantation. Furthermore, no differences in survival rates were observed up to 1 year post-transplantation. However, a higher incidence of drug related side-effects was found in the monoclonal group. Caution should be exercised after the initial dose of monoclonal antithymoglobulins due to the small risk of respiratory and hemodynamic compromise. The results of this review underscore the importance of conducting a large, multi-centered, randomized clinical trial to address this issue.
References
Kormos RL, Armitage JM, Dummer JS, Miyamoto Y, Griffith BP, Hardesty RL. Optimal perioperative immunosuppression in cardiac transplantation using rabbit antithymocyte globulin. Transplantation 1990;49:306–311.
Kobashigawa JA, Stevenson LW, Brownfield E, Moriguchi JD, Kawata N, Hamilton M, Minkely R, Drinkwater D, Laks H. Does short-course induction with OKT3 improve outcome after heart transplantation A randomized trial. J Heart Lung Transplant 1993;12:250–258.
Kormos RL, Herlan DB, Armitage JM, Stein K, Kaufman C, Zeevi A, Duquesnoy R, Herdesty RL, Griffith BP. Monoclonal versus polyclonal antibody therapy for prophylaxis against rejection after heart transplantation. J Heart Lung Transplant 1990;9:1–10.
Costanzo-Nordin MR, O'Sullivan EJ, Johnson MR, Winters GL, Pifarre R, Radvany R, Zucker MJ, Scanlon PJ, Robinson JA. Prospective randomized trial of OKT3 vs. horse antithymocyte globulin-based immuno-suppressive prophylaxis in heart transplantation. J Heart Transplantation 1992;9:306–315.
Renlund DG, O'Connell JB, Gilbert EM, Hammond ME, Burton NA, Jones KW, Karwande SV, Doty DB, Menlove RL, Herrick CM, Lee HR, Gay WA, Bristow MR. A prospective comparison of murine monoclonal CD-3 (OKT3) antibody-based and equine antithymocyte globulin-based rejection prophylaxis in cardiac transplantation. Decreased rejection and less corticosteroid use with OKT3. Transplantation 1989;47:599–605.
Griffith BP, Kormos RL, Armitage JM, Dummer JS, Hardesty RL. Comparative trial of immunoprophylaxis with RATG vs. OKT3. J Heart Transplant 1990;9:301–305.
MacDonald PS, Mundy J, Keogh AM, Chang VP, Spratt PM. A prospective randomized study of prophylactic OKT3 vs. equine antithymocyte globulin after heart transplantation increased morbidity with OKT3. Transplantation 1993;55:110–116.
Menkis AH, Powell AM, Novick RJ, McKenzie FN, Kostuk WJ, Pflugfelder PW, Brown JE, Rochon J, Chow LH, Stiller C. A prospective randomized controlled trial of initial immunosuppression with ALG vs. OKT3 in recipients of cardiac allografts. J Heart Lung Transplantation 1992;11:569–576.
Ippoliti G, Negri M, Abelli P, Rovati B, Di Franco L, Grossi P, Minoli L, Ascari E, Vigano M. Preoperative prophylactic OKT3 vs. RATG. A randomized clinical study in heart transplantation. Transplantation Proceedings 1991;23:2272–2274.
Laske A, Gallino A, Schneider J, Bauer EP, Carrel T, Pasic M, Von Segesser LK, Turina MI. Prophylactic cytolytic therapy in heart transplantation: Monoclonal vs. polyclonal antibody therapy. J Heart Lung Transplantation 1992;11:557–563.
Kirklin JK, Bourge RC, White-Williams C, Naftel DC, Thomas FT, Thomas JM, Phillips MG. Prophylactic therapy for rejection after cardiac transplantation: a comparison of rabbit antithymocyte globulin and OKT3. J Thorac Cardiovasc Surg 1990;99:716–724.
Ladowski JS, Dollon T, Schatzlein MH, Peterson AC, Deschner WP, Beatty L, Sullivan M, Scheeringa RH, Clark WR. Prophylaxis of heart transplant rejection with either antithymocyte globulin-Minnesota antilymphocyte globulin-, or an OKT3-based protocol. J Cardiovasc Surg (Torino) 1993;34:135–140.
Balk AH, Meeter K, Simoons ML, Brouwer RM, Zondervan PE, Mochtar B, Bos E, Weimar W. Polyclonal vs. monoclonal rejection prophylaxis after heart transplantation: a randomized study. Transplant International 1992;5:S476–S479.
Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. Brit Med J 1994;309:1286–1291.
Jadad AR, Moore RA, Carrol D. Assessing the quality of reports of randomized clinical trials: is blinding necessary. Control Clin Trials 1996;17:1–12.(Michel Haddad, Fahad S. A)