Research in Allied Health

Research in Allied Health
Tacrolimus or Cyclosporine:
Which is the better choice for immunosuppressant therapy following lung transplantation.
By: Ima Geniustudent
Rough draft exemplar, AMA style
Tacrolimus has been used successfully in many different types of organ transplant procedures. It has become an approved immunosuppressant drug for most of these types of transplants. However, because of the much lower number of lung transplants performed it has taken much longer to complete testing of tacrolimus in lung transplants. These lung recipients are being given less potent medications that are already registered for use with lung transplant surgeries when a much better drug is available. Tacrolimus has been proven efficient as a rescue immunosuppressant following cyclosporine. It has also been proven efficient as a primary immunosuppressant following lung transplantation in adult mongrel dogs. (Hirai, et al. 1992)
It is now time to begin using tacrolimus as a primary immunosuppressant medication with human lung transplant patients.
Drug regulation agencies require clinical trials for each type of organ transplantation for an immunosuppressant drug before it can be registered as a primary medication for that specific transplant procedure. Because of the low number of lung transplants that are performed it takes that much longer for enough clinical data to be obtained on a new immunosuppressant.
Lungs are one of the most commonly rejected organs following transplantation surgery. Statistics have shown that an acute rejection rate for lung transplant patients is 54%, whereas a renal transplant has only a 17% rate of rejection. (Knoop, et al 2004). There are no human leukocyte antigen (HLA) matching tests available on lung tissue and, unlike all other transplanted organs, the lungs are permanently exposed to environmental air containing fumes, toxins and infectious agents. (Knoop, et al. 2004). With this higher rejection rate, it is obvious that more potent immunosuppressant drugs are needed and should be used sooner in post surgical recovery of lung transplant recipients. (van den Berg, et al. 1999).
Immunosuppressant drugs have improved greatly over the years. Before cyclosporine, the current drug of choice, there was no long term survival chances for lung recipients. Even with cyclosporine, an acute rejection is treated in nearly 60% of patients within the first 12 months post surgery (Parekh, et al. 2004). In a 1996 study, 15 patients that had been experiencing refractory rejections while taking cyclosporine were switched to a newer immunosuppressant called tacrolimus as a rescue therapy. Of these 15 patients, 11 of them experienced a complete reversal of rejection (Onsager, et al. 1999). The data from this study also suggested that a time delay before initiating tacrolimus rescue therapy resulted in poorer outcomes for the patients.
In many studies, the patients that experience rejection while taking cyclosporine make complete recoveries when rescued with tacrolimus. In a study where 34 patients were started on cyclosporine therapy and 28 patients were given tacrolimus as the primary therapy, the survival rate of the 2 groups after 1 year were 70.6% and 92.3% respectively (Kur, et al. 1999). Furthermore, in a study performed in 1995, an equal number of patients received either tacrolimus or cyclosporine. Significantly more of the cyclosporine patients had to be transferred to the tacrolimus group due to rejection episodes (13 of 67) than tacrolimus patients being transferred to cyclosporine (2 of 66) (Keenan, et al. 1995). Other similar studies have been performed over the years with varying results; however Tacrolimus seems to be the better immunosuppressant and should be used as the primary therapy.
Problem Statement
Tacrolimus provides broader protection of transplanted organs
DepVar Transplanted organs
IndepVar Rejection risk, long term protection, cost, recipient age
Review of Literature
Top notch immunosuppressant drugs are the critical factor in the survival of lung transplant recipients. As stated by C. Knoop in 2004 (160) “The rationale of induction therapy is to use the strongest immunosuppressant at the time the risk is highest, that is, in the first few weeks following transplantation.” This statement was referring to all types of organ transplant procedures, but I believe it to be a most accurate statement when dealing with lung transplantation. The risk of rejection in lung transplant patients is so much greater than in other types of organ transplants that there is an even greater need for more potent immunosuppressant medications for these procedures. New medications are currently being developed and tested by the pharmaceutical companies, but by the time they are approved for use in lung transplant patients many patients are beyond recovery. If newer immunosuppressive drugs that are not registered for use in lung transplantation are deemed necessary, these drugs should not be withheld. If a new drug is proven beneficial in other forms of transplantation, researchers and doctors should be encouraged to use them before clinical trials in lung transplantation have been finalized (van den Berg, et al. 1999).
In studies done by Robert Mentzer (1998) and David Onsager (1999) where patients experiencing acute rejection were switched to Tacrolimus from Cyclosporine they each found that the rejection condition in most patients were reversed. In the patients that did not improve, the authors believe that the level of rejection was too severe to be reversed. “Data suggests that a time delay in initiation of tacrolimus results in a poorer outcome for lung transplant patients with refractory rejection” (Onsager, et al. 1999, 453). “Lung transplant patients may receive more benefit if rescued earlier” (Mentzer, et al. 1998, 109).
New developments and advancements in immunosuppressive therapy depend on the use of tacrolimus, a more potent immunosuppressant (Kur, et al. 1999 and Onsager, et al. 1999), being used earlier in the treatment. Why not start the induction therapy with tacrolimus? Some studies found that the efficacy of tacrolimus was equivalent to cyclosporine (Zuckermann, et al. 2003). Most studies (Knoop, et al. 2004, van den Berg, et al. 1999, Kur, et al. 1999, Mentzer, et al. 1998 and Onsager, et al. 1999) show tacrolimus to be a more potent immunosuppressant drug compared to cyclosporine. Researchers also believe that there would be no more side effects than already exhibited in patients on cyclosporine (Reichenspurner, et al. 1999)
Also, using tacrolimus earlier in the study would be beneficial to the patient.
To begin a study of the efficacy of tacrolimus following lung transplant procedures, I would first go through the university IRB for approval and follow all the guidelines set up by HIPPA to assure that all test subjects’ information is protected. I would then use a positivistic approach to partially replicate a study performed by David R. Onsager, MD et al. between 1993 and 1996. Onsager used a quantitative approach to determine that tacrolimus was indeed the best immunosuppressive medication to be given to lung recipients that were experiencing rejection while taking cyclosporine. The study I would perform would follow these same avenues, except that I would start the patients on the tacrolimus therapy and if needed, change them over to cyclosporine.
At the University of Wisconsin at Madison Hospital, 49 patients underwent lung transplant surgery. Because of the low number of lung transplant procedures that are performed, any lung recipient would have the choice to enroll in this drug trial. Immunosuppressant (cyclosporine) was initiated at the time of transplantation via IV. The patients began oral dosing of cyclosporine as soon as they were able to handle it, and their blood levels were closely monitored to maintain the desired 12-hour trough levels. The patients underwent surveillance and pulmonary function testing when they complained of fever, fatigue or dyspnea on exertion. When lung rejection was diagnosed a high-dose steroid was administered. Rejection was diagnosed histologically or by a persistently low FEV1 value. Those patients that were diagnosed histologically were transferred to tacrolimus therapy at roughly three months and the patients depending on the FEV1 value were not transferred until 15 months on average. When this steroidal procedure failed to reduce the severity of rejection, patients were then transferred to a tacrolimus therapy.
A statistical analysis was performed on the rate of decline in FEV/month after tacroliums rescue was initiated. Rejection was reversed in 73% of the patients that were switched over to tacrolimus therapy. The patients that were switched over to tacrolimus earlier showed the most significant decrease in declining FEV levels. An autoregressive error structure was performed to account for variance in individuals. The significance of rejection was evaluated with the Fisher exact test. The degree of rejection was used to place the data in an ordinal fashion for a non-parametric statistical analysis. The Kruskal-Wallis test was then used to evaluate the difference in time after transplantation to conversion to tacrolimus rescue therapy.
Although tacrolimus was responsible for the reversal of rejection in these lung transplant patients, many of them subsequently developed obliterative bronchiolitis. The patients succumbed to this infection. A delay in initiating rescue therapy likely contributed to this outcome. This again stresses that earlier rescues are required.
In all of the papers I read, I kept finding a common statement. Earlier diagnosis of rejection in lung transplant recipients is required to effectively “rescue” them. Another commonality is that tacrolimus is no worse regarding side effects than cyclosporine. Therefore, if the medication has proven itself as a rescue drug with no serious side effects, it should then be used as the primary immunosuppressant medication for lung transplant recipients. With lungs being among the most commonly rejected organs following transplant procedures, it would make sense to use the most potent drug available as the initial therapy. When another immunosuppressant comes along and is clinically proven better and registered with other organ transplants, it should not be withheld due to lack of clinical trial with lung recipients. It should be pushed into use with lung transplants as swiftly as possible.
Hirai,T. Et al. (1992). The immunosuppressive effect of FK506 on canine lung transplantation. Journal of Thoracic Cardiovascular Surgery, Jun;103(6):1127-1135.
Keenan, RJ. Et al. (1995). Clinical trial of tacrolimus versus cyclosporine in lung transplantation. Annals of Thoracic Surgery. Sep;60(3):580-584/
Knoop, C. Et al. (2004). Immunosuppressive therapy after human lung transplantation. European Respiratory Journal, (23);159-171.
Kur, F. Et al. (1999). Tacrolimus (FK506) as primary immunosuppressant after lung transplantation. Thoracic Cardiovascular Surgery, Jun;47(3):174-178.
Mentzer, Robert M. Et al. (1998). Tacrolimus as a rescue immunosuppressant after heart and lung transplantation. Transplantation, (65)109-113.
Onsager, David R. Et al. (1999). Efficacy of Tacrolimus in the treatment of refractory rejection in heart and lung transplant recipients. Journal of Heart and Lung Transplantation, 18:448-455.
Parekh, K, and E Trulock. (2004). Use of cyclosporine in lung transplantation. Transplantation Proceedures, March; 36 (2 supplements):318-322
Reichenspurner, H.. Et al. (1999). Optimization of the immunosuppressive protocol after lung transplantation. Transplantation, Jul 15;68(1):67-71.
Van den Berg, JWK. Et al. (1999). New immunosuppressive drugs and lung transplantation: last or least? Thorax, 54:550-553.
Zuckermann, A, Et al. (2003). Cyclosporine A versus tacrolimus in combination with mycophenolate mofetil and steroids as primary immunosuppresseion after lung transplantation: one-year results of a 2-center prospective randomized trial. Journal of Thoracic Cardiovascular Surgery, Apr;125(4):784-786.

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