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Meta-Analysis: The Efficacy of Strategies To Prevent Organ Disease by Cytomegalovirus in Solid Organ Transplant Recipients

Andre C. Kalil, MD; Josh Levitsky, MD; Elizabeth Lyden, MS; Julie Stoner, PhD; and Alison G. Freifeld, MD
[+] Article and Author Information

From University of Nebraska Medical Center, Omaha, Nebraska.


Acknowledgments: The authors thank Elaine Litton for providing outstanding administrative support and Patricia A. Kalil for critical review of the manuscript.

Grant Support: None.

Potential Financial Conflicts of Interest: Consultancies: A.G. Freifeld (Enzon); Honoraria: A.G. Freifeld (Pfizer Inc., Enzon, Merck & Co. Inc.); Grants received: A.G. Freifeld (Ortho-McNeil); Grants pending: A.G. Freifeld (Astellas).

Requests for Single Reprints: Andre C. Kalil, MD, University of Nebraska Medical Center, 985400 Nebraska Medical Center, Omaha, NE 68198-5400; e-mail, akalil@unmc.edu.

Current Author Addresses: Drs. Kalil and Freifeld: University of Nebraska Medical Center, 985400 Nebraska Medical Center, Omaha, NE 68198-5400.

Dr. Levitsky: Northwestern Memorial Hospital, 303 East Chicago Avenue, Chicago, IL 60611.

Ms. Lyden and Dr. Stoner: University of Nebraska Medical Center, 985350 Nebraska Medical Center, Omaha, NE 68198-4350.

Author Contributions: Conception and design: A.C. Kalil. Analysis and interpretation of the data: A.C. Kalil, J. Levitsky, E. Lyden, J. Stoner, A.G. Freifeld. Drafting of the article: A.C. Kalil, E. Lyden, J. Stoner, A.G. Freifeld. Critical revision of the article for important intellectual content: A.C. Kalil, J. Levitsky, E. Lyden, J. Stoner, A.G. Freifeld. Final approval of the article: A.C. Kalil, J. Levitsky, E. Lyden, J. Stoner, A.G. Freifeld. Statistical expertise: E. Lyden, J. Stoner. Collection and assembly of data: A.C. Kalil, J. Levitsky.


Ann Intern Med. 2005;143(12):870-880. doi:10.7326/0003-4819-143-12-200512200-00005
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The process of study selection is shown in Figure 1. Two studies (3839) met exclusion criterion 1, 1 study (40) met exclusion criterion 2, 4 studies (4144) met exclusion criterion 3, and 14 studies (4558) met exclusion criterion 6. A list of studies that met exclusion criterion 5 is available from the authors on request. Eleven trials involving 1582 patients (14, 3237, 5962) were selected for the universal prophylaxis analysis, and 6 trials involving 398 patients (6368) were selected for the preemptive therapy analysis. One of the 11 universal prophylaxis trials only administered prophylaxis for 28 days (32). Three trials were double-blind (32, 35, 59), and 6 trials were placebo-controlled (14, 32, 35, 37, 59, 62). Allocation concealment was adequate in 5 trials (14, 32, 35, 59, 62) and was unclear or inadequate in the remaining trials. We assessed the length of follow-up as adequate in 7 trials (14, 33, 35, 59, 6365) but noted that most trials did not report the exact timing of outcome events.

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Figure 2.
Universal prophylaxis trials (top) and preemptive trials (bottom): effect on cytomegalovirus (CMV) organ disease.

Arrows represent CIs < 0.1 or > 10. Box sizes represent the weight of each trial. For the prophylaxis trials, the test for overall effect was  = 6.92 (  < 0.001) and the test for heterogeneity was chi-square = 4.94 (  = 0.90; I = 0%). For the preemptive trials, the test of overall effect was  = 1.86 (  = 0.003) and the test for heterogeneity was chi-square = 5.80 (  = 0.33; I = 14%).

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Figure 3.
Universal prophylaxis trials (top) and preemptive trials (bottom): effect on allograft rejection.

Arrows represent CIs < 0.1 or > 10. Box sizes represent the weight of each trial. For the prophylaxis trials, the test for overall effect was  = 2.52 (  = 0.012) and the test for heterogeneity was chi-square = 12.71 (  = 0.123; I = 37%). For the preemptive trials, the test of overall effect was  = 2.21 (  = 0.026) and the test for heterogeneity was chi-square = 2.73 (  = 0.603; I = 0%).

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Figure 4.
Universal prophylaxis trials (top) and preemptive trials (bottom): effect on mortality.

Arrows represent CIs < 0.1 or > 10. Box sizes represent the weight of each trial. For the prophylaxis trials, the test for overall effect was  = 2.15 (  = 0.032) and the test for heterogeneity was chi-square = 3.44 (  = 0.94; I = 0%). For the preemptive trials, the test of overall effect was  = 0.12 (  = 0.90) and the test for heterogeneity was chi-square = 0.87 (  = 0.93; I = 0%).

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Figure 5.
Universal prophylaxis trials of acyclovir, 3.2 g/d (top), and ganciclovir, 3 g/d (bottom).

Arrows represent CIs < 0.1 or > 10. Box sizes represent the weight of each trial. For the prophylaxis trials with acyclovir, the test for overall effect was  = 4.44 (  < 0.001) and the test for heterogeneity was chi-square = 1.30 (  = 0.97; I = 0%). For the prophylaxis trials with ganciclovir, the test of overall effect was  = 3.89 (  < 0.001) and the test for heterogeneity was chi-square = 0.93 (  = 0.63; I = 0%). CMV = cytomegalovirus.

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Meta-analysis: The efficasy of strategies to prevent CMV organ disease in SOT
Posted on January 17, 2006
Nina Singh
University of Pittsburgh
Conflict of Interest: None Declared

Meta-analysis: The efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients

To the Editors:

The meta-analysis by Kalil et al addresses an important issue (1). However, we caution that the conclusions may be potentially misleading because of significant limitations of the studies, variability in the duration of prophylaxis and the length of follow-up in the published studies, and the selection of trials for the meta-analysis. The studies by Conti et al and Hibberd et al (2, 3) cannot truly be considered preemptive therapy as prophylactic use of an antiviral agent in patients receiving antilymphocytic antibodies is based on the likelihood of CMV infection during augmented immunosuppression rather than on the detection of CMV replication or viremia. That the basis of indirect sequelae of CMV is intermittent viral replication, as proposed by the authors, may not be applicable to these patients in whom therapeutic intervention is employed before rather than upon detection of viral replication, as in preemptive therapy.

Our major concern is the sample size in the "˜subgroup' analyses. For example, the R-/D+ group, in which they document no statistically significant benefit for preemptive therapy for CMV disease, comprised only 33 patients with 3 disease events (Figure 2). Rather than conclude that preemptive therapy is not as optimal as universal prophylaxis for specified subgroups, we believe that a more rational conclusion would have been that there were insufficient numbers in the preemptive therapy group. The conclusions regarding the impact of preemptive therapy on secondary end-points e.g., opportunistic infections and mortality are also of concern (1). While these outcomes have not been systematically assessed in CMV antiviral trials in general, the number of preemptive therapy studies, in particular with regards to secondary outcomes is so few as to preclude meaningful assessment of the impact of preemptive therapy on indirect sequelae of CMV. For example, if trials that are based on the use of preemptive therapy upon viral detection are considered, then the analysis of the effect of this approach on mortality in their meta-analysis (Figure 4) would have included only two studies involving a total of only 72 patients (4, 5).

Regardless, examination of the graphical data show that 95% confidence intervals of all comparisons have a considerable degree of overlap. If the null hypothesis is that preemptive therapy and universal prophylaxis are equivalent, then the data presented do little to refute it. We however, agree with the authors that only a carefully conducted randomized trial can discern the efficacy of two approaches with regards to direct and indirect outcomes associated with CMV.

Nina Singh, MD Marilyn M. Wagener, MPH Infectious Diseases Section VA Medical Center Pittsburgh, PA

REFERENCES

1.Kalil AC, Levitsky J, Lyden E, Stoner J, Freifeld AG. Meta- analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients. Ann Intern Med 2005; 143:870-880.

2.Conti D, Tolkoff-Rubin NE, Baker GPJr, Doran M, Cosimi AB, DelMonico F, Auchincloss HJr, Russell PS, Rubin RH. Successful treatment of invasive fungal infection with fluconazole in organ transplant recipients. Transplantation 1989; 48:692-695.

3.Hibberd PL, Tolkoff-Rubin NE, Conti D, Stuart F, Thistlewaite JR, Snydman DR, Freeman R, Lorber MI, Rubin RH. Preemptive ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus antibody-positive renal transplant recipients. A randomized controlled trial. Ann Intern Med 1995; 123:18-26.

4.Rayes N, Seehofer D, Schmidt CA, Oettle H, Müller AR, Steinmüller T, Settmacher U, Bechstein WO, Neuhaus P. Prospective randomized trial to assess the value of preemptive oral therapy for CMV infection following transplantation. Transplantation 2001; 72:881-885.

5.Sagedall S, Nordal KP, Haartmann A, Midtvedt K, Foss A, Asberg A, Degré M, Fauchald P, Rollag H. Pre-emptive therapy of CMV pp65 antigen positive renal transplant recipients with oral ganciclovir; a randomized, comparative study. Nephrol Dial Transplant 2003; 18:1899-1908.

Conflict of Interest:

None declared

Meta-Analysis: The Efficacy of Strategies to Prevent CMV Organ Disease in SOT
Posted on January 25, 2006
Andre C Kalil
University of Nebraska
Conflict of Interest: None Declared

We do appreciate the comments from Dr Singh and Ms Wagener, but we have several disagreements that need to be addressed.

First, their statement ""¦we caution that the conclusions may be potentially misleading because of significant limitations of the studies, variability in the duration of prophylaxis and the length of follow-up"¦and the selection of trials"¦" We do not agree with this statement because the trial design limitations, duration of follow-up and prophylaxis were thoroughly evaluated by sensitivity analyses (1) and the meta-analysis' conclusions remain unchanged.

Second, their statement "The studies by Conti et al and Hibberd et al cannot truly be considered preemptive therapy"¦" Interestingly, the titles of these two studies start with "Preemptive ganciclovir therapy"¦" (2,3). Based on the objectives and quality of these two trials, we decided that they should be included in our analysis. Nonetheless, because of the more immunosuppressed population selected for these two studies and the potential differences in the design of the preemptive therapy (pointed by Singh and Wagener), we also performed a sensitivity analysis (not included in the manuscript). The overall results for CMV organ disease in the preemptive analysis remain similar and statistically significant (OR, 0.24 [0.07 to 0.85], p=0.01; Breslow-Day test p=0.19).

Third, their statement "Our major concern is the sample size in the "˜subgroup' analyses." As seen in any well-designed large clinical trial or meta-analysis, the sample size for the subgroup analyses is always a potential concern because no single trial or meta-analysis is likely to be adequately powered for all subgroup analyses. The studies are powered for the "˜group', not for the "˜subgroups'. Therefore, we agree with Singh and Wagener's concerns about the subgroup power.

Fourth, their statement "Rather than conclude that preemptive therapy is not as optimal as universal prophylaxis for specified subgroups"¦" We did not make this statement in any section of our paper and we did not make conclusions based on subgroup results only. What we actually said in our discussion section is found in the final paragraph "Our results suggest that universal prophylaxis may be the preferred method of treatment because of its reduction in post-transplantation CMV organ disease, its reduction in bacterial/fungal opportunistic infections, allograft rejection, and death. However, a prospective trial"¦needs to be done to confirm our findings". This statement is based on the results from the primary and secondary outcome analyses.

Fifth, their statement ""¦then the analysis of the effect of this approach on mortality in their meta-analysis would have included only two studies involving a total of only 72 patients." This is incorrect. The two studies included 140 patients.

In conclusion, we agree that both strategies are very effective in preventing CMV organ disease, but the debate about the differences in the effect magnitude and costs between both strategies can only be brought to a close by a randomized trial.

Andre C Kalil, M.D., Julie Stoner, Ph.D.

University of Nebraska, Nebraska Medical Center Omaha, NE 68198-5400

1. Kalil AC, Levitsky J, Lyden E, Stoner J, Freifeld AG. Meta- analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients. Ann Intern Med. 2005;143(12):870-80.

2. Hibberd PL, Tolkoff-Rubin NE, Conti D, Stuart F, Thistlethwaite JR, Neylan JF, Snydman DR, Freeman R, Lorber MI, Rubin RH. Preemptive ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus antibody-positive renal transplant recipients. A randomized controlled trial. Ann Intern Med. 1995;123(1):18-26.

3. Conti DJ, Freed BM, Singh TP, Gallichio M, Gruber SA, Lempert N. Preemptive ganciclovir therapy in cytomegalovirus-seropositive renal transplants recipients. Arch Surg. 1995;130(11):1217-21

Conflict of Interest:

None declared

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