The frequent nocturnal hemodialysis intervention did not meet the prespecified criteria for statistical significance for either coprimary composite outcome of death/LV mass or death/PHC. Frequent nocturnal hemodialysis substantially improved the control of hyperphosphatemia and of systolic blood pressure, did not produce detectable improvements in any of the remaining prespecified main secondary outcomes relative to the three times per week group, and tended to increase vascular access events. These results differ from the FHN Daily Trial, as in that study there was a statistically significant benefit of more frequent hemodialysis for both coprimary outcomes. The other secondary outcome findings and vascular access findings of the FHN Daily Trial were similar to those found in this trial.16
There are several possible explanations for the nonsignificant effects of the intervention on the coprimary end points, some of which differ between the LV mass and PHC outcomes.
First, the estimated treatment effect on the mean change in LV mass (−10.9 g) should be interpreted in the context of its wide 95% CI (−23.7 to +1.8). The CI contains the value of 0, corresponding to no treatment effect. At the same time, changes in LV mass close to the center of the interval (for example, 10 g) have been associated with differences in mortality of up to 50% in observational studies of dialysis patients.17,18
Thus, when taken by themselves, the results of the FHN Nocturnal Trial neither prove nor disprove the hypothesis that frequent nocturnal dialysis leads to clinically important reductions in LV mass. On the basis of the dropout rates and variability in the change in LV mass observed in the study, one would have needed a sample size of 275 patients to obtain 80% power to detect a mean effect on LV mass of 10 g, and 125 patients to detect a mean change of 15 g.
Second, the FHN nocturnal LV mass results can be interpreted in the context of previous studies. The FHN nocturnal confidence interval contains the estimated effects of the six times per week interventions in the recently published FHN Daily Trial16
of −13.8 g (95% CI −21.8 to −5.8 g) and the shorter-term Culleton trial15
of −15.3 g (95% CI −29.6 to −1.0 g). Hence, the differences between the estimated effects on LV mass across the three randomized trials of frequent hemodialysis are consistent with chance variation. Given the positive effects on LV mass demonstrated in the two previous randomized trials of frequent dialysis, the inconclusive result of the FHN Nocturnal Trial could be interpreted as consistent with the hypothesis that nocturnal dialysis reduces LV mass to some extent. Although more sophisticated statistical analyses may provide additional hypothesis-generating information, the only method by which this question can be properly answered is to perform an adequately powered randomized clinical trial.
Finally, it is possible that differences in study population or design may have contributed to differences between our LV mass findings and those of the Culleton trial.15
The FHN Nocturnal Trial included a larger proportion of incident patients (~50%) than the Culleton trial. The median duration of dialysis in the Culleton trial was 5.2 years compared with 3.45 years in the FHN Nocturnal Trial. Although the Culleton trial did not report residual renal function, the difference in both the percentage of incident patients and the mean duration of dialysis suggests that urine volume and renal solute clearances are likely to have been substantially larger in the FHN trial, thus reducing the relative contribution of the dialysis regimens to total solute and fluid removal. Design differences between the trials include follow-up time (12 months in the FHN Nocturnal vs 6 months in the Culleton trial) and the method for measuring LV mass (which included papillary muscles in the Culleton trial but not in the FHN Nocturnal Trial).
Both the conventional and frequent hemodialysis treatments were performed primarily at home. The mean PHC score for the entire FHN Nocturnal cohort (both frequent nocturnal and conventional arms) increased by 2.4 points (95% CI 0.3 to 4.5 points, P
= 0.02). However, the increase in the PHC score was similar between the two groups, with an estimated mean difference of only 0.6 points, corresponding to less than ~1/10th of the s.d. of PHC, with a 95% CI from −3.4 to 4.7 points (). Hence, although the overall increase in the mean PHC in both treatment groups is consistent with a positive effect of the change in venue from in-center hemodialysis at baseline to home hemodialysis during follow-up, our data provide no suggestion that the PHC score was improved by the frequent dialysis therapy itself. Although nocturnal dialysis has been reported to be associated with improved quality of life in some previous observational studies,11
our observation of an increase in the PHC in both treatment arms suggests that these differences may have resulted in part from differences in venue (home for frequent nocturnal hemodialysis vs in-center hemodialysis for conventional) rather than the therapy itself.
Adverse effects of more frequent nocturnal home hemodialysis included a trend for more frequent vascular access complications, which were due to an increase in vascular access procedures other than failures. This observation is most likely secondary to the more frequent use of the vascular access with more frequent hemodialysis. Hypotensive episodes were less common in the frequent nocturnal arm, which could reflect either the lower ultrafiltration rates used or differences in the reporting rates for hypotension between the two study arms.
The strengths of the FHN Nocturnal Trial include the relatively diverse patient population in terms of demographics and comorbidity, excellent separation between trial arms for both weekly dialysis dose, as measured by stdKt/Vurea,
and the number of prescribed treatments per week, the use of blinded cardiac magnetic resonance imaging measurements for assessment of LV mass, and the wide variety of secondary outcomes examined, including adverse events. In contrast, previous observational studies have methodological limitations, including selection bias, nonrandomized trial study design, minimal data on access complications, and other potential safety and feasibility issues.19
The major limitations of the trial were the relatively small sample size and the lower adherence to the dialysis prescription in the frequent nocturnal arm, both of which reduced the power of the study. Recruitment was difficult as the initial protocol forced random assignment to in-center versus home hemodialysis; most patients interested in this study uniformly wanted to be dialyzed at home. Recruitment increased when patients were offered a choice between two different types of home hemodialysis, but was still difficult in part because of the proximity of other home hemodialysis programs offering the use of new home hemodialysis technologies and also because of barriers to acceptance of home hemodialysis therapies.20
In addition, only 87.3% of the patients who were randomized completed 12 months of follow-up and had measures of both coprimary outcomes. Moreover, ~25% of patients in the frequent nocturnal arm performed less than five hemodialysis treatments per week. In addition, patients in the FHN Nocturnal Trial were younger, had more residual renal function, and were less likely to be African American,21
thus limiting generalizability to the broader population of patients receiving maintenance hemodialysis therapy. Finally, the trial was not powered to determine the effect of the intervention on mortality or hospitalization rate. Owing to difficulty in recruitment, the power to detect modest differences in the coprimary composite outcomes and the main secondary outcomes was lower than anticipated.
In conclusion, frequent nocturnal home hemodialysis, compared with three times per week hemodialysis, did not result in significant benefits on the coprimary composite outcomes of death/LV mass or death/PHC. Moderate effects on LV mass may have gone undetected because of a small sample size; PHC improved in both groups, perhaps secondary to the effect of performing dialysis at home. Frequent nocturnal hemodialysis improved control of hyperphosphatemia and hypertension, but tended to increase vascular access events.