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Ann Thorac Surg 1995;60:580-584
© 1995 The Society of Thoracic Surgeons
Divisions of Cardiothoracic Surgery and Pulmonary and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentReferences |
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Methods. Between October 1991 and May 1994, 133 single-lung and bilateral-lung recipients were randomized to receive either cyclosporine (n = 67) or tacrolimus (n = 66). The two groups were similar in age, sex, and underlying disease.
Results. One-year and 2-year survival rates were similar in the two groups, although the trend was toward increased survival with tacrolimus. Acute rejection episodes per 100 patient-days were fewer (p = 0.07) in the tacrolimus group (0.85) than in the cyclosporine group (1.09). Obliterative bronchiolitis developed in significantly fewer patients in the tacrolimus group (21.7%) compared with the cyclosporine group (38%) (p= 0.025), and there was greater freedom from obliterative bronchiolitis over time for patients receiving tacrolimus (p < 0.03). Significantly more cyclosporine-treated patients (n = 13) required crossover to tacrolimus than tacrolimus-treated patients to cyclosporine (n = 2) (p = 0.02). The switch to tacrolimus controlled persistent acute rejection in 6 of 9 patients. The overall incidence of infections was similar in the two groups, although bacterial infections were more common with cyclosporine (p = 0.0375), whereas the risk of fungal infection was higher with tacrolimus (p < 0.05).
Conclusions. This trial demonstrates the advantage of tacrolimus in reducing the risk of obliterative bronchiolitis, the most important cause of long-term morbidity and mortality after lung transplantation.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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The success of solid-organ transplants depends on the ability of potent immunosuppressive agents to prevent and treat allograft rejection. The use of cyclosporin–based immunosuppression regimens has resulted in 1-year survival rates of between 70% and 74% for patients having isolated lung transplantation [1]. Infection is the leading cause of death in the first year after transplantation and, in many instances, results from the need for aggressive treatment of persistent acute rejection. Obliterative bronchiolitis (OB), often combined with infection, is the leading cause of death more than 1 year after transplantation. Refractory acute rejection is a known risk factor for the development of OB [2], which is recognized as the histologic manifestation of chronic rejection. The toxicities of cyclosporine, in particular impaired renal function and hypertension, limit increases in dosage to treat rejection.
For editorial comment, see page 495.
Tacrolimus (FK 506), a macrolide antibiotic, has been demonstrated to have impressive immunosuppressive properties and is 10 to 100 times more potent than cyclosporine. Previous clinical trials in liver and kidney transplantation [3–5] have confirmed its efficacy in preventing and treating graft rejection. A previous randomized trial comparing tacrolimus and cyclosporine in liver transplant patients [6] demonstrated improved graft and recipient survival rates for patients receiving tacrolimus.
Encouraged by these results and by our own experience in cardiac transplantation with tacrolimus [7, 8], we initiated a prospective, randomized clinical trial comparing tacrolimus with cyclosporine in patients undergoing isolated lung transplantation. Preliminary analysis [9] with the first 74 recipients indicated fewer episodes of acute rejection in patients receiving tacrolimus. This report summarizes the results of the completed trial.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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).
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Patients receiving tacrolimus were begun at a dosage of 0.025 mg • kg-1 • d-1 given by continuous intravenous infusion. The dosage was increased as necessary to achieve a serum level of 1.0 to 1.8 ng/mL as measured by the FK 506 enzyme-linked immunosorbent assay technique of Tamaura and colleagues [10]. When the tacrolimus assay (Abbott Inc.) became available, target levels were determined to be 10 to 20 ng/mL. Once recipients were able to tolerate oral medications, tacrolimus was given twice daily at a dosage of 0.15 mg • kg-1 • d-1
Recipients randomized to cyclosporine were initially given 2.5 mg • kg-1 • d-1 by continuous intravenous infusion and then by oral administration when tolerated. The dosage of cyclosporin A was adjusted to maintain a target serum level of 750 to 1,000 ng/mL (Abbott TDx method).
Rejection Protocol
Allograft rejection was detected by clinical symptoms, chest radiograph, decline in breathing capacity, and biopsy results. Histologic confirmation of at least grade 2 rejection or active OB [11] on transbronchial biopsy was required to initiate treatment except in the early postoperative period. Surveillance biopsy specimens were obtained at least once during the initial hospitalization and at 3-month intervals thereafter unless clinically indicated.
Initial episodes of acute rejection were treated by intravenous methylprednisolone, 1,000 mg/d, for 3 successive days. Persistent or refractory (greater than three episodes) rejection and OB were treated with cytolytic therapy using antithymocyte globulin.
Study Variables and Statistical Analyses
Comparisons of patient survival and freedom from OB were made by Kaplan-Meier life-table analysis with log rank and Wilcoxon testing to determine the presence of significant differences. Incidences of infection (bacterial, viral, and fungal) and acute rejection, both expressed as the number of episodes per 100 patient-days, were compared using the Mann-Whitney test. As a measure of drug toxicity, renal impairment, based on serum creatinine levels, was determined 1 year after transplantation and compared using Student's t test. Fifteen patients were switched from one drug to the other. These patients were not included in the survival estimates but were included in the analysis of all other variables up to the time of the switch. The significance of the rate of crossover was determined by 
2 analysis. A significance level of p equal to 0.05 was used in all analyses.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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). The major causes of death in the perioperative (0–30 days) period were ischemic lung injury and sepsis (Table 2). Infection, primarily pneumonia, was the leading cause of death in the first year, and respiratory failure from OB, with or without pneumonia, was responsible for six of nine late deaths.
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The population considered to be at risk for OB was defined as recipients surviving at least 2 months after transplantation. Of the 60 patients who received tacrolimus and were at risk, only 13 (21.7%) had development of OB as diagnosed by transbronchial biopsy. In contrast, OB developed in 19 patients given cyclosporine including 3 who were switched from cyclosporine to tacrolimus after the diagnosis of OB was made. This represented 38% of patients given cyclosporine (19/50) a significantly greater incidence (p = 0.025) than in the tacrolimus group. Kaplan-Meier life-table analysis also demonstrated significantly greater freedom from OB at more than 1 year postoperatively for recipients treated with tacrolimus (p < 0.03) (Fig 2). The mean time to first presentation of OB was slightly longer in the tacrolimus group (350 ± 45 days) compared with the cyclosporine group (311 ± 36 days).
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Infection
The overall incidence of infections in the two groups was similar, although bacterial pneumonias were significantly more common among patients receiving cyclosporine (0.92 ± 2.16 episodes/100 patient-days) than in the tacrolimus group (0.33 ± 0.82 episode/100 patient-days) (p = 0.0375). In contrast, the incidence of fungal infections was greater in the tacrolimus group (0.49 ± 1.77) compared with the cyclosporine group (0.10 ± 0.28) (p < 0.05). The incidence of cytomegalovirus infections was similar in the two groups, as was the degree of donor and recipient serologic matching.
Systemic Side Effects
Transient renal dysfunction was frequently observed in the early postoperative period in patients in both groups. Concomitant administration of prostaglandin E1 (0.01 mg • kg-1 • d-1) limited the level of dysfunction. At 1 year after transplantation, the extent of renal impairment was similar in the two groups with serum creatinine levels averaging 1.95 ± 0.72 mg/mL for patients receiving tacrolimus and 1.68 ± 0.6 mg/mL for cyclosporine-treated recipients. The frequency of systemic hypertension requiring medication for control was similar in the two groups. Recipient acceptance of the immunosuppressive agent was notably greater in patients receiving tacrolimus because of the absence of gingival hyperplasia and hirsutism.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Of potentially greater importance, however, is the finding that tacrolimus was associated with a reduction in the appearance of OB, the histologic manifestation of chronic rejection. As we [12] and others have reported, OB is the most significant long-term complication after lung transplantation. Respiratory failure from OB or pneumonia superimposed on the damage caused by OB was responsible for 67% of the late deaths and 10% of deaths within the first year in this trial. The reduced incidence of OB among patients receiving tacrolimus undoubtedly contributed to the trend toward increased 1-year and 2-year survival for these recipients. With longer follow-up, significantly improved long-term survival may well be noted. The finding of a reduced incidence of chronic rejection is of particular importance in lung transplantation because of the high operative risk and poorer survival rates for retransplantation [13]. The continued trend toward a reduced frequency of acute rejection episodes among patients given tacrolimus is also important, as persistent or refractory acute rejection has been demonstrated to be a significant risk factor for the development of OB [12].
The potency of tacrolimus as an immunosuppressive agent was again demonstrated by its ability to perform as ``rescue'' therapy for patients with persistent acute rejection while receiving adequate dosages of cyclosporine. Significantly more patients required switching from cyclosporine to tacrolimus than vice versa, and the majority of the recipients were switched to control rejection. Neither patient initially randomized to receive tacrolimus required crossover for rejection. The success of this rescue therapy is consistent with results achieved in liver [14] and renal [15] transplantation.
The improved potency of any immunosuppressive agent must be tempered with the risk of infection secondary to aggressive rejection therapy. Mortality from infection accounted for 50% of the deaths in the first year after transplantation. The overall infection rate was similar in the two groups. Tacrolimus was associated with fewer episodes of bacterial infections but greater numbers of fungal disease. The difference in the prevalence of infections with each medication was reflected in the risk of death from that infection: fungal infections were responsible for three (43%) of seven of the first-year deaths caused by infection in the tacrolimus group and bacterial infection, four (80%) of five deaths resulting from infection in the cyclosporine group. These characteristics are important when designing improved antimicrobial protocols for both prophylaxis and treatment of infection.
Transient renal impairment was observed in the majority of patients in both groups. The impact of both immunosuppressive agents on chronic renal dysfunction was similar with serum creatinine levels being comparable 1 year after transplantation. The incidence of systemic hypertension and the need for pharmacologic control were also similar in each group. Neither drug was associated with a significant incidence of neurotoxicity. Hirsutism and gingival hyperplasia were unknown in the tacrolimus group, which was particularly attractive for the patients receiving this drug.
In summary, this completed prospective, randomized trial comparing tacrolimus and cyclosporine as primary immunosuppressive therapy demonstrates the efficacy of tacrolimus in reducing the incidence of OB. This form of chronic rejection is the most significant cause of long-term morbidity and mortality; hence freedom from OB should ultimately translate into prolonged survival after lung transplantation. The ability of tacrolimus to perform as a ``rescue'' therapy for patients with persistent or refractory rejection was also confirmed in this study. The difference in profile of infectious complications between the two groups suggests that closer attention should be paid to modifying antimicrobial regimens during times of augmented immunosuppression. The availability of tacrolimus represents an important advance in the management of lung transplant recipients in terms of both the potential for prolonged survival and the improved quality of life.
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Address reprint requests to Dr Keenan, Section of Thoracic Surgery, University of Pittsburgh, Suite 300 L. S. Kaufmann Building, 3471 Fifth Ave, Pittsburgh, PA 15213.
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References |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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