Tacrolimus monotherapy in adult cardiac transplant recipients: intermediate-term results

IMMUNOSUPPRESSION

Tacrolimus Monotherapy in Adult Cardiac Transplant Recipients: Intermediate-Term Results David A. Baran, MD,a Leal Segura, BS,a Sudhir Kushwaha, MD,b Mary Courtney, RN,a Rhodora Correa, RN,a John T. Fallon, MD,c Judy Cheng, PharmD,a Steven L. Lansman, MD,d and Alan L. Gass, MDa Background: Tacrolimus (FK506) is a macrolide antibiotic that inhibits T-cell activation and proliferation. To date, all published trials have used tacrolimus and steroids in combination with either azathioprine or mycophenolate mofetil. Previous experience with pediatric cardiac transplant patients at our institution suggested that use of tacrolimus alone provides an adequate level of immunosuppression and that withdrawal of steroids is readily achieved in most recipients. Methods: Between January 1, 1996, and July 7, 1999, we performed 77 adult cardiac transplants. Forty-three of these patients received tacrolimus and prednisone as primary immunosuppression, without azathioprine or mycophenolate mofetil. Thirty-two of the 43 patients started on tacrolimus have been weaned off steroids and are maintained on monotherapy. These latter patients form the basis of this report. Results: The mean time for achieving monotherapy was 246 ⫾ 127 days (range, 106 to 730). Grade ⱖ 2 rejection occurred at 0.40 episodes per patient in the first 90 days (a combination of Grades 2 and 3A/3B rejections). The freedom from treated rejection (includes all 3A/3B and Grade 2 rejection in the first 90 days) was 69% at 90 days and 52% at 1 year. One patient (of 32) had documented cytomegalovirus infection (gastritis) diagnosed at 8 months post-transplant. We observed 1 case of transplant vasculopathy and 1 case of post-transplant lymphoproliferative disorder during the follow-up period. Conclusions: Our results show that use of tacrolimus alone after steroid weaning provides effective immunosuppression with low incidence of rejection, cytomegalovirus infection, transplant arteriopathy, or post-transplant lymphoproliferative disease. J Heart Lung Transplant 2001;20:59–70.

C

ardiac transplantation is now the definitive treatment for end-stage congestive heart failure with 1-, 5-, and 10-year survival of 79%, 71%, and 43%

respectively.1 Advances in immunosuppressive agents provide one of the main reasons for this success. The introduction of cyclosporine in 1978

From the aZena and Michael A. Wiener Cardiovascular Institute, USA, cDepartment of Pathology, USA, and dDepartment of Cardiovascular Surgery, Mount Sinai Hospital, New York, New York; and bDivision of Cardiology, University of North Carolina, Chapel Hill, North Carolina. Reprint requests: David A. Baran, MD, Mount Sinai Hospital, Zena and Michael A. Wiener Cardiovascular Institute,

1 Gustave L. Levy Place, Box 1030, New York, New York 10029. Telephone: 212-241-5215. Fax: 212-289-5971. Copyright © 2001 by the International Society for Heart and Lung Transplantation. 1053-2498/01/$–see front matter PII S1053-2498(00)00237-0

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resulted in significant improvement in graft and patient survival.2,3 Triple therapy with cyclosporine, azathioprine, and prednisone has since become the standard immunosuppressive regimen for preventing rejection. Tacrolimus (FK506) is a macrolide antibiotic that inhibits T-cell activation and proliferation and inhibits production of other cytokines. The product of Streptomyces tsurubaensis fermentation, FK506 was discovered in 1984 and first used in clinical studies in 1988 at the University of Pittsburgh.4 –7 It is now widely used in renal,8 liver,9,10 and lung transplants.11,12 Laboratory and clinical data suggest that it may be a more potent immunosuppressant than cyclosporine, and it appears free of some of the side effects, in particular, hirsutism and gingival hyperplasia. All published trials in adult recipients to date have used tacrolimus in combination with either azathioprine or mycophenolate mofetil as well as with steroids. Previous experience with pediatric cardiac transplant patients at our institution suggested that use of tacrolimus alone provides an adequate level of immunosuppression and that withdrawal of steroids is readily achieved in most recipients.13 Since 1996, we have used tacrolimus and steroids as initial immunosuppression for the majority of patients who undergo cardiac transplantation. We have developed a protocol with aggressive steroid weaning, allowing most of the patients to remain on tacrolimus alone. The present study describes the outcomes for these patients as well as comparative data from other institutions.

METHODS Patient Population Between January 1, 1996, and July 7, 1999, we performed 77 adult cardiac transplants. Forty-three of these patients received tacrolimus and prednisone as primary immunosuppression, without azathioprine or mycophenolate mofetil. The transplant team chose immunosuppressive therapy, preferentially giving tacrolimus to patients who did not have evidence of significant hemodynamic instability or renal failure. Figure 1 shows the breakdown of patients in the overall cohort. Three of the initial tacrolimus patients subsequently converted to cyclosporine-based triple therapy: 1 patient secondary to renal insufficiency, 1 for hemolytic uremic syndrome, and 1 secondary to labile serum levels.

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Twenty-nine of 77 patients started cyclosporinebased triple therapy especially early in the experience with tacrolimus. Of these, about 50% (14 patients) converted to tacrolimus at a mean of 182 ⫾ 129 days post-transplant (range, 9 to 452). Five patients never received tacrolimus or cyclosporine because of early post-operative deaths. We have weaned from steroids 32 of the 43 patients that we had started on tacrolimus and have maintained them on monotherapy. These latter patients form the basis of this report.

Statistical Analysis We conducted all analysis with Statview software (SAS Institute) on an IBM-compatible PC computer. We used Microsoft Excel 97 (Microsoft; Redmond, Washington) to generate graphs.

Tacrolimus Laboratory Assay We performed whole blood levels using fluorescence polarization immunoassay on an Abbott IMX instrument.

Immunosuppressive Protocol Patients received methylprednisolone 500 mg IV during the surgery. Post-operatively, they received methylprednisolone 125 mg IV every 8 hours for 3 doses. Patients then started prednisone 0.3 mg/kg in 2 daily doses. Within 24 hours transplant, each patient received 1 mg of tacrolimus (Fujisawa) as a “test” dose either through the nasogastric tube or by mouth. Low-dose dopamine (1.5 to 2 ␮g/kg/min IV) was started before the first dose. We based subsequent tacrolimus dosing on the initial trough level, renal function, and clinical status. Target trough levels in the first 7 to 10 days were 10 to 15 ng/ml. The target level beyond Day 7 was 15 to 20 ng/ml, limited only by worsening renal function. Table I outlines a suggested schedule for initiating tacrolimus. We derived this table from our clinical practice, but have not prospectively validated it. It is a useful guide but must be modified by individual patient factors, especially the administration of medications such as fluconazole or diltiazem, which antagonize tacrolimus metabolism. The purpose of a “test dose” is to allow the clinician to predict the appropriate next dose of tacrolimus without rigorous pharmacokinetics, which is unpredictable with the initial oral dose.14 We suggest that a slow rise in tacrolimus level is desirable. Therefore to achieve a steady rise, we treat low levels with a

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FIGURE 1 Flow chart detailing immunosuppressive choice for 77 patients transplanted during study period. AZA, azathioprine; MMF, mycophenolate mofetil.

total daily increased dose of 2 mg. This contrasts with the published literature that emphasizes speed to therapeutic blood levels (either with tacrolimus IV or with immediate weight-adjusted dosing). We reserved cytolytic therapy (muromonab, OKT3) for patients with severe post-operative hemodynamic instability or patients with acute renal failure. During this study, 2 of 32 patients received OKT3 therapy, 1 of whom was a retransplant and

the other required support with a left ventricular assist device.

Biopsy Schedule We performed weekly endomyocardial biopsies for the first month, biweekly for the next 2 months, and then each 3 to 4 weeks for the next 3 months, with a tapering schedule thereafter. Patients underwent an average of 7 endomyocardial biopsies during the

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TABLE I Suggested tacrolimus dosing scheme Days on tacrolimus

If the level is . . .

0 (Start of therapy) 1

— 0–1.9 2–3.9 4–5.9 ⱖ6 0–1.9 2–3.9 4–5.9 ⱖ6 0–1.9 2–3.9 4–5.9 6–9.9 ⱖ10 0–1.9 2–3.9 4–5.9 6–9.9 ⱖ10 0–1.9 2–3.9 4–5.9 6–9.9 ⱖ10 0–1.9 2–3.9 4–5.9 6–9.9 ⱖ10 0–1.9 2–3.9 4–5.9 6–9.9 ⱖ10

2

3

4

5

6

7

The suggested morning dose is . . . Test dose ⫽ 1 m 1 1 0.5 HOLD 2 2 2 1 3 3 2 2 Same as previous 5 4 4 3 Same as previous 6 5 4 4 Same as previous 8 7 6 5 Same as previous 10 9 8 6 Same as previous

first 90 days post-transplant and a total of 16 biopsies in the first year.

Treatment of Rejection and Steroid Tapering We uniformly graded endomyocardial biopsies using the International Society for Heart and Lung Transplantation (ISHLT) scale.15 Pathologists were unaware of the immunosuppressive regimen. We considered biopsies with Grades 0, 1A, or 1B as negative. We tapered steroids by 5 mg until achieving a daily dose of 10 mg. We subsequently tapered doses by 2.5 mg with each negative biopsy, until discontinuation of steroids. We treated Grade 2 rejection only within the first 90 days or if accompanied by hemodynamic compromise. We treated Grades 3A or 3B rejection without

dose

dose

dose

dose

dose

The suggested evening dose is . . . NONE 1 1 0.5 HOLD 2 1 1 1 3 2 2 2 Same as 5 4 3 3 Same as 6 5 4 3 Same as 8 7 6 4 Same as 10 9 7 5 Same as

previous dose

previous dose

previous dose

previous dose

previous dose

hemodynamic compromise with either 3 days of methylprednisolone 1,000 mg IV, or with prednisone 1 mg/kg orally for 3 days, depending on clinical status and rejection history. We treated hemodynamically significant rejection with 3 days of methylprednisolone 1000 mg IV and with OKT3. We used mycophenolate mofetil and azathioprine only in cases of persistent rejection and usually discontinued them after resolution. After treatment of rejection, we immediately resumed steroids at the previous dose, or did not use them if patients were on monotherapy.

CMV Prophylaxis We determined the type of prophylactic medication for cytomegalovirus (CMV) with a risk assessment.

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TABLE II Demographics Tacrolimus/prednisone N Male Female Ischemic Non-ischemic Mean age at transplant Mean donor age Mean ischemic time HLA-DR Match Recipient blood group O Recipient blood group A Recipient blood group B Recipient blood group AB Donor recipient weight ratio Left ventricular assist device bridge UNOS I at time of transplant

32 23, with 2 female donors, 21 male donors 9, 3 female donors, 6 male donors 17 15 52 ⫾ 12.5 years 26.7 ⫾ 9.1 years 165 ⫾ 48 minutes 25% with at least 1 DR match 14, all received O donors 11, 10/11 received A donors 4, all received B donors 3, 1 AB, 1 B, and 1 A donor 1.15 ⫾ 0.26 3 31

UNOS, United Network of Organ Sharing.

We routinely test patients who undergo cardiac transplant and organ donors for IgG anti-CMV antibodies. Patients who test negative for anti-CMV antibodies are at particular risk for acquiring acute CMV infection if they receive an organ from a CMV-positive donor. These patients received intravenous ganciclovir for 3 to 5 days and oral ganciclovir (Cytovene) for 6 months. Patients who were CMV negative and received CMV-negative allografts did not require anti-CMV prophylaxis. Remaining patients received acyclovir 800 mg orally 4 times a day for 6 months.

RESULTS Table II describes the study cohort and includes 3 patients supported pre-operatively with left ventricular assist devices and 1 retransplant. Before transplant, the United Network for Organ Sharing listed all but 1 patient as Status I. The mean time to achieve monotherapy was

246 ⫾ 127 days (range, 106 to 730). We removed 1 patient from azathioprine at 565 days, and slowly weaned 1 from prednisone at 730 days. Neither patient had rejection after the first post-transplant year, nor did they suffer rejection after achieving monotherapy.

Patients Selection for Tacrolimus We considered all adult patients transplanted during the time of the study for tacrolimus as the primary immunosuppressant. Fourteen of 29 patients who started on cyclosporine-based triple therapy eventually converted to a tacrolimus regimen as well, yielding 58 of 77 (75%) patients on tacrolimus. A future manuscript will provide a complete discussion of patients converted from cyclosporine to tacrolimus.

Rejection Profile Table III presents the breakdown of biopsy results. During the first 90 days post-transplant, patients

TABLE III Biopsy breakdown ISHLT biopsy grade ⬍2 2 3A/3B 4 Totals

1st 90 days posttransplant

90–365 days posttransplant

0–365 days on tacrolimus monotherapy

219 (92%) 7 (3%) 11 (4.5%) 0 237

295 (85%) 32 (9%) 19 (5.4%) 0 346

188 (90%) 15 (7%) 5 (2.4%) 0 208

ISHLT, International Society for Heart and Lung Transplantation.

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FIGURE 2 Stacked bar graph depicting percent of negative (grade ⬍ 2), intermediate(Grade 2), and high-grade (Grade 3A/3B) biopsies using the International Society for Heart and Lung Transplantation scale.

received 237 biopsies, with the following distribution: 219 ISHLT grade ⬍ 2 (92%), 7 Grade 2 (3%), and 11 Grade 3A/3B (4.6%). We observed no Grade 4 biopsies. After 90 days, and up until the first post-transplant year, 346 biopsies were performed, with the following breakdown: 295 ISHLT grade ⬍ 2 (85%), 32 Grade 2 (9%), and 19 Grade 3A/3B (5.4%). We observed no Grade 4 biopsies. Analysis of the 208 biopsies performed during the first 365 days after achieving tacrolimus monotherapy showed 188 ISHLT grade ⬍ 2 (90%), 15 Grade 2 (7%), and 5 Grade 3A/3B (2.4%). We found no Grade 4 biopsies. Figure 2 graphically presents these results. Each vertical bar represents 100 percent of the biopsies performed in a specific period, and the patterns represent the contribution of negative, intermediate-, and high-grade biopsies to the total. Table IV shows the rejection frequency expressed as episodes per patient. Grade ⱖ 2 rejection occurred at 0.40 episodes per patient in the first 90 days (a combination of Grades 2 and 3A/3B rejections). Grade ⱖ 3A rejection occurred at 0.43 episodes per patient during the remainder of the first post-transplant year. We also used life-table analysis to analyze the incidence of rejection, resulting in the freedom-fromrejection statistic. Figure 3 shows the plot of freedom

from all treated rejection, as well as freedom from Grade 3A/B rejection in our cohort. The freedom from Grade 3A/3B rejection was 75% at 90 days and 53% at 1 year. The freedom from treated rejection (includes all Grade 3A/3B and Grade 2 rejection in the first 90 days) was 69% at 90 days and 52% at 1 year.

TABLE IV Frequency of rejection (rejections per patient) Variable Grade 2 rejection, 1st 90 days after transplant Grade 2 rejection, 90–365 days after transplant Grade ⱖ 3A rejection, 1st 90 days Grade ⱖ3A rejection, 90–365 days after transplant Grade 2 rejection, 1st post-transplant year Grade ⱖ3A rejection, 1st post-transplant year Treated rejection, 1st 90 days after transplant Treated rejection, 1st post-transplant year

Frequency per patient 0.12 0.78 0.28 0.43 0.91 0.72 0.40 0.84

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FIGURE 3 Actuarial freedom from rejection during the first year post-transplant.

CMV Infection We routinely screen patients who undergo cardiac transplant and organ donors for IgG anti-CMV antibodies. Patients who test negative for anti-CMV antibodies are at particular risk for acquiring acute CMV infection if they receive an organ from a CMV-positive donor. Five of 32 patients were in this high-risk group. Five of 32 patients who were CMV negative received a CMV-negative allograft. Patients who demonstrate anti-CMV antibodies pretransplant are at lower risk of post-transplant CMV infection. Seven of these patients received a CMVnegative allograft, and 15 received a CMV-positive organ. One patient (a CMV-positive patient, who received a CMV-positive allograft) had documented CMV infection (gastritis) diagnosed at 8 months.

Renal Function No patient required dialysis during this study, and no patient required discontinuance of therapy because of renal dysfunction. We used intravenous dopamine at “renal” doses based on anecdotal experiences with patients before 1996. This has not been prospectively studied, and we cannot estimate the contribution of this medication to the initial tolerability of oral tacrolimus.

Low-dose dopamine is free of side-effects in perioperative management of heart transplant patients and may have beneficial effects.

Transplant Arteriopathy One of the 32 patients developed transplant vasculopathy during the follow-up period. One had a mid-left anterior descending lesion at the early post-transplant angiogram, but this progressed to a discrete 95% left anterior descending lesion at 1 year, which was subsequently treated with percutaneous intervention.

Survival No patient in this cohort has died, with a posttransplant follow-up of 726 ⫾ 366 days (range, 221 to 1,502 days). The mean follow-up after achieving tacrolimus monotherapy was 479 ⫾ 347 days (range, 55 to 1,210 days). Figure 4 is a Kaplan-Meier plot of 1-year survival for patients started on tacrolimus as initial immunosuppression, patients converted to tacrolimus, and patients maintained on cyclosporine throughout the study period. The tacrolimus survival curves were significantly better (93% for both primary tacrolimus and conversion at 1 year) than that of the cyclosporine group (47% at 1 year) (p ⬍ 0.0001 by Mantel-Cox test).

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FIGURE 4 Kaplan-Meier survival plot sub-divided by immunosuppressive regimen (initial tacrolimus, or cyclosporine-based regimen).

Malignancy One patient developed post-transplant lymphoproliferative disease 18 months after transplant, which responded to reduction of tacrolimus blood levels and adjunctive chemotherapy.

Cost Table 5 lists the average wholesale prices of various transplant immunosuppressant medications. The daily cost of cyclosporine 200 mg/day (Neoral brand, Novartis) along with mycophenolate mofetil dose (2,000 mg/day), and prednisone (5 mg) is $29.90.

The daily cost of tacrolimus alone (7 mg total dose) is $19.25.

DISCUSSION Prospective, randomized studies and non-randomized series have investigated tacrolimus use. The first use of tacrolimus in clinical heart transplants occurred at the University of Pittsburgh in October 1989, which has reported the longest experience with tacrolimus triple therapy.16 Our results show that excellent clinical outcomes are achieved with tacrolimus alone, without the

TABLE V Average wholesale price of various transplant medications Drug name

Cost per unit dose

Average daily dose

Daily cost

Neoral (cyclosporine, Novartis) Azathioprine, generic Mycophenolate mofetil Tacrolimus Prednisone Daclizumab

$5.94 (100 mg) $1.17 (50 mg) $4.50 (500 mg) $2.75 (1 mg) $0.02 (5 mg) $418.20 (25 mg)

200 mg 150 mg 2,000 mg 7 mg 5 mg 75 mg ⫻ 6 doses

$11.88 $3.51 $18.00 $19.25 $0.02 $2509.20 (3 months)

Source: Average wholesale price, 1999 drug topics redbook, Medical Economics, Montvale, New Jersey.

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FIGURE 5 Use of tacrolimus and cyclosporine regimens during the study period, 1996 to 1999.

need for routine cytolytic induction therapy. This tacrolimus monotherapy does not appear to compromise rates of rejection, infection, or transplant vasculopathy in this initial patient group. The incidence of rejection episodes that required treatment was 7.6% during the first 90 days post-transplant and 5.4% thereafter. During the first full year after achieving monotherapy, only 2.4% of biopsies required treatment. Rejection episodes per patient were also low as shown in Table IV. Tacrolimus monotherapy results in low levels of CMV infection (1 patient out of 32), which is a likely consequence of the lower intensity of immunosuppression in our patients. Only 1 patient developed post-transplant lymphoproliferative disease 1.5 years after transplant. Development of significant allograft arteriopathy occurred in 1 patient during the follow-up period and was successfully treated with an intra-coronary stent. However, this case was not purely transplant vasculopathy, because the allograft had a demonstrated left anterior descending lesion at the time of transplant. Furthermore, no patient has died, with the longest follow-up of 1,210 days. Most of the ongoing immunosuppression studies in heart transplantation focus on higher levels of immu-

nosuppression, with either adjuncts to conventional triple therapy or more potent anti-lymphocytic drugs (such as various formulations of rapamycin)17,18 designed to augment or replace azathioprine or mycophenolate mofetil. Tacrolimus monotherapy represents a significant departure from conventional regimens because we successfully avoided the use of chronic azathioprine or mycophenolate mofetil coupled with an aggressive steroid weaning protocol. We give patients who achieve monotherapy only pulse steroid therapy without a tapering phase. The intermediate-term success of this approach suggests that researchers should focus attention on ways to minimize immunosuppression while maintaining low rates of rejection and infection in the near term and low rates of malignancy in the long term. In addition, cost appears equivalent and may be significantly less expensive with the use of newer agents such as mycophenolate mofetil or daclizumab. Figure 4 presents the 1-year Kaplan-Meier survival plots for the patients in the overall cohort who initially received tacrolimus, or were maintained on cyclosporine therapy. The 1-year survival is worse (47% at 1 year) in the cyclosporine group, but this was not a randomized study of

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TABLE VI Previous studies with tacrolimus n on TAC

Study European Multicenter Pilot

Majority steroidfree at 1 year

TAC dosing

AZA/MMF

54

No

Oral 0.3 mg/kg/day

AZA

15

No

Oral 0.15 mg/kg/day in 2 divided doses

AZA

Pittsburgh’s intermediate term results16

122 (42 pediatric, 80 adults)

No

0.05 mg/kg/day IV continuous infusion, with a switch to oral TAC, 0.2–0.3 mg/kg/day

AZA

MMF and tacrolimus: Meiser et al22

45

Yes

IV 0.01–0.02 mg/kg/day for 2–3 post-transplant days, then oral 0.03–0.01 mg/ kg/day

MMF

Tacrolimus vs cyclosporine, Meiser et al14

43

Yes

Oral 0.3 mg/kg/day,

AZA

Rinaldi et al

19

21

AZA, azathioprine; CMV, cytomegalovirus; MMF, mycophenolate mofetil; TAC, tacrolimus; RATG, rabbit anti-thymocyte globulin.

cyclosporine vs tacrolimus. We present this data only to emphasize that the patients who did not receive tacrolimus during the study interval were quite ill and received standard (as opposed to unproven) therapy. Figure 5 shows the use of cyclosporine vs tacrolimus at our institution during the study period. Based on interim analyses of the data, our use of tacrolimus has steadily increased. Table VI lists several studies using tacrolimusbased therapy and includes the incidence of rejection, adjunctive medications, and tacrolimus dosing. The literature suggests that tacrolimus is quite effective against rejection, but nephrotoxicity can be a significant problem, especially when intravenously administered.19 In addition, although some studies report a significant percentage of steroid weaning, most patients remain on triple therapy. Recently, Beniaminovitz et al20 reported the results of an open-label, randomized, pilot trial that examined the use of daclizumab in conjunction with cyclosporine-based triple therapy with mycophenolate mofetil and steroids. Daclizumab is a humanized antibody to the interleukin-2 receptor on activated T lymphocytes. Use of this drug is thought to confer selective immunosuppression by selectively preventing T-cell activation and therefore T-cell mediated B-cell activation.

The frequency of rejection in this study (including Grades 2 and 3A/B) was 0.67 overall, with a frequency of 0.19 during quadruple therapy and 0.50 after antibody induction (90 days). Outcomes with tacrolimus monotherapy compare favorably with those achieved in the prior study using quadruple therapy. In the first 3 months when the incidence of allograft rejection is typically highest, the rates of Grade 2 and Grade 3A/B rejection in our cohort were 0.12 and 0.28, respectively, nearly matching the results of the more intensive therapy in the daclizumab study.20 In addition, the percent freedom from rejection is similar between the studies, despite the vast difference in anti-rejection regimen. Meiser et al14 recently reported a randomized comparison of tacrolimus and cyclosporine, both used as triple therapy with azathioprine and steroids. The mean follow-up was 27 months, and the freedom from rejection rates were 20.9% with tacrolimus and 0% (all patients with at least 1 rejection) with cyclosporine therapy. In addition, the tacrolimus group had a 27.9% rate of hemodialysis at 3 months post-transplant (although the cyclosporine group had a 23.3% rate). The European Multicenter Pilot Trial used a weight-adjusted tacrolimus dose, resulting in a 31.5% rate of transient, early hemodialysis.19 No patient in our cohort required hemodialysis, and

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Infections 1st year post-transplant

Target blood level

26.3% freedom from treated rejection at 1 year

3/5 centers

38.9% incidence of viral infections

15–25 ng/ml

0.12 ⫾ 0.35 high-dose group

All patients, 7 days of RATG

1.73 ⫾ 1.27 episodes per patient

15–25 ng/m

47% freedom from rejection at 3 months, and 42% at 1 year

None

Not stated

15–30 ng/ml

None

37.7% incidence of viral infections

13–18 ng/ml

None

20.9% incidence of CMV infection

15–25 ng/ml

1.33 ⫾ 1.18 in first 15 patients (no mycophenolate blood-level monitoring), 0.1 ⫾ 0.31 in remaining 30 patients 1.33 ⫾ 0.99 per patient 21% freedom from rejection 1st year

therapy was never interrupted because of renal insufficiency. We largely attribute this to a conservative scheme of tacrolimus oral dosing and the realization that achieving a therapeutic tacrolimus level over 4 to 5 days is preferable to reaching rapid acceptable blood levels at the expense of renal function.

Limitations This is a retrospective review of a cohort selected for tacrolimus monotherapy based on the discretion of the transplant team, although every patient was considered eligible. However, the demographics of the group indicate a high-risk cohort, with 3 left ventricular assist patients and 1 retransplant. The rate of HLA-DR matching (at least a single DR locus) was only 25%. In addition, nearly all patients were in the United Network for Organ Sharing Status I at the time of transplant. This study does not compare cyclosporine and tacrolimus therapy. We do not intend it to address equivalence or superiority of tacrolimus to cyclosporine-based regimens. However, the finding that tacrolimus monotherapy was safely achieved in a significant number of patients is provocative.

CONCLUSIONS Allograft rejection, infection, and transplant arteriopathy limit survival after cardiac transplant. Adequately suppressing the immune system without increasing the risk of infection or late malignancy

remains the major challenge of post-transplant management. The interplay of cellular rejection, immunosuppressive therapy, and development of transplant arteriopathy are still not completely understood. Our results show that using tacrolimus alone after steroid weaning provides potent immunosuppression without significant incidence of rejection, CMV infection, transplant arteriopathy, or post-transplant lymphoproliferative disease. In addition, cost is comparable to cyclosporine-based triple therapy with azathioprine, and is significantly less expensive with use of newer agents such as mycophenolate mofetil or daclizumab. The relatively short follow-up tempers these conclusions and limits our ability to make definitive statements. We have achieved excellent survival in this otherwise high-risk cohort of patients, and the long-term follow-up data will hopefully continue to validate this approach. Future studies should examine the overall benefits of tacrolimus monotherapy as compared with cyclosporine and newer agents such as daclizumab and rapamycin. REFERENCES 1. Hosenpud JD, Bennett LE, Keck BM, Fiol B, Boucek MM, Novick RJ. The Registry of the International Society for Heart and Lung Transplantation: sixteenth official report— 1999. J Heart Lung Transplant 1999;18:611–26. 2. Calne RY, White DJ, Thiru S, et al. Cyclosporin A in patients

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5.

6.

7.

8.

9.

10.

11.

12.

13.

Baran et al.

receiving renal allografts from cadaver donors. Lancet 1978; 2:1323–7. Calne RY, Rolles K, White DJ, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 1979; 2:1033– 6. Fung JJ, Todo S, Jain A, et al. Conversion from cyclosporine to FK 506 in liver allograft recipients with cyclosporinerelated complications. Transplant Proc 1990;22:6 –12. Fung JJ, Todo S, Tzakis A, et al. Conversion of liver allograft recipients from cyclosporine to FK 506-based immunosuppression: benefits and pitfalls. Transplant Proc 1991;23:14 – 21. Kino T, Hatanaka H, Miyata S, et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 1987;40:1256 – 65. Kino T, Hatanaka H, Hashimoto M, et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) 1987;40:1249 –55. Jensik SC. Tacrolimus (FK 506) in kidney transplantation: three-year survival results of the US multicenter, randomized, comparative trial. FK 506 Kidney Transplant Study Group. Transplant Proc 1998;30:1216 – 8. Pichlmayr R, Winkler M, Neuhaus P, et al. Three-year follow-up of the European Multicenter Tacrolimus (FK506) Liver Study. Transplant Proc 1997;29:2499 – 502. Busuttil RW, Holt CD. Tacrolimus (FK506) is superior to cyclosporine in liver transplantation. Transplant Proc 1997; 29:534 – 8. Wiebe K, Harringer W, Franke U, et al. FK506 rescue therapy in lung transplantation. Transplant Proc 1998;30: 1508 –9. Mentzer RM Jr, Jahania MS, Lasley RD. Tacrolimus as a rescue immunosuppressant after heart and lung transplantation. The U.S. Multicenter FK506 Study Group. Transplantation 1998;65:109 –13. Herzberg GZ, Rossi AF, Courtney M, et al. Usefulness of tacrolimus versus cyclosporine after pediatric heart transplantation. Am J Cardiol 1998;82:541–3.

The Journal of Heart and Lung Transplantation January 2001 14. Meiser BM, Uberfuhr P, Fuchs A, et al. Single-center randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of acute myocardial rejection. J Heart Lung Transplant 1998;17:782– 8. 15. Billingham ME, Cary NR, Hammond ME, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant 1990;9:587–93. 16. Pham SM, Kormos RL, Hattler BG, et al. A prospective trial of tacrolimus (FK 506) in clinical heart transplantation: intermediate-term results. J Thorac Cardiovasc Surg 1996; 111:764 –72. 17. Kahan BD, Julian BA, Pescovitz MD, Vanrenterghem Y, Neylan J. Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in Caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group. Transplantation 1999;68: 1526 –32. 18. Groth CG, Backman L, Morales JM, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999;67:1036 – 42. 19. Reichart B, Meiser B, Vigano M, et al. European Multicenter Tacrolimus (FK506) Heart Pilot Study: one-year resultsd— European Tacrolimus Multicenter Heart Study Group. J Heart Lung Transplant 1998;17:775– 81. 20. Beniaminovitz A, Itescu S, Lietz K, et al. Prevention of rejection in cardiac transplantation by blockade of the interleukin-2 receptor with a monoclonal antibody. N Engl J Med 2000;342:613–9. 21. Rinaldi M, Pellegrini C, Martinelli L, et al. FK506 effectiveness in reducing acute rejection after heart transplantation: a prospective randomized study. J Heart Lung Transplant 1997;16:1001–10. 22. Meiser BM, Pfeiffer M, Schmidt D, et al. Combination therapy with tacrolimus and mycophenolate mofetil following cardiac transplantation: importance of mycophenolic acid therapeutic drug monitoring. J Heart Lung Transplant 1999; 18:143–9.