Author + information
- Kim ten Dam, MD,
- Ingo Germund, MD,
- Markus Khalil, MD,
- Willem A. Helbing, MD, PhD,
- Narayanswami Sreeram, MD, PhD and
- Floris E.A. Udink ten Cate, MD, PhD∗ ()
- ↵∗Department of Pediatric Cardiology, Amalia Children’s Hospital, Radboud University Medical Center, Geert Grooteplein Zuid 10, PO Box 9101, 6500 HB, Nijmegen, the Netherlands
We read with interest the recent paper by Itkin et al. (1). The authors are to be commended for their effort. However, the results should be viewed in the context of specific limitations.
First, the serum albumin level is frequently being used as a surrogate endpoint in Fontan patients with protein-losing enteropathy (PLE) (1,2). For a surrogate endpoint to be a meaningful substitute for clinical outcome, the changes induced by a therapeutic intervention (liver lymphatic embolization) on the surrogate (serum albumin level) are expected to reflect alterations in a clinically meaningful outcome measure (remission, major adverse events, survival) (3). As a surrogate endpoint, serum albumin level, however, does not fulfill this important criterion (3). A recent study demonstrated that serum albumin level was not able to discriminate between PLE patients who survived and those who did not (2). Furthermore, PLE in Fontan patients is a complex and heterogeneous disease. Patients often have fluctuating serum albumin levels not induced by an adjustment in their treatment regimen. Although enteric protein loss is the hallmark of PLE, other important cardiac and noncardiac features may all significantly contribute to clinical outcome (2). Even when, in theory, the serum albumin level would be a valid surrogate endpoint in Fontan research, the therapeutic effect on clinical outcome in the study by Itkin et al. (1) would have been overestimated because the effect on the surrogate, although statistically significant, was not of sufficient size and duration (mean change in albumin level 1.50 ± 1.03 g/dl, need for several procedures, duration of 4 months) in those patients with a treatment effect to predict a meaningful alteration in clinical outcome (1,3). Therefore, the results of liver lymphatic embolization should be interpreted with caution, because this surrogate endpoint can yield misleading conclusions. Although the authors also used PLE symptoms to assess the effect of the intervention, it is not clear how symptomatic improvement was quantified. When used subjectively, the results of symptomatic improvement may be biased.
Second, the Central Illustration and Table 3 (1) are somewhat confusing. Table 3 shows that the current albumin level of Patient #5 is 5.2 g/dl. However, the central illustration demonstrates a current albumin level of only 4.0 g/dl, thus showing a significant decrease in albumin over time. In addition, the albumin level of Patient #4 seems lower, and the current albumin level of Patient #1 seems higher (around 2.2 g/dl) than stated in Table 3 (1).
Third, the duodenum as the site of lymph leakage in Fontan patients with PLE has not been reported previously (1). However, duodenal lymphatic abnormalities have been observed in patients with celiac disease and PLE (4). Did the authors exclude celiac disease in their patients?
Taken together, the study by Itkin et al. (1) underscores the urgent need to develop validated outcome measures to assess disease severity and to quantify the true effectiveness of a therapeutic intervention in Fontan patients with PLE.
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
- Itkin M.,
- Piccoli D.A.,
- Nadolski G.,
- et al.
- John A.S.,
- Johnson J.A.,
- Khan M.,
- Driscoll D.J.,
- Warnes C.A.,
- Cetta F.
- Perisic V.N.,
- Kokai G.