Correspondence
Paricalcitol, Calcitriol, and Survival of Patients Undergoing Hemodialysis
N Engl J Med 2003; 349:1971-1972November 13, 2003
- Article
To the Editor:
The rate of death from any cause among patients undergoing dialysis in the United States remained steady at 17 to 18 percent per year between 1996 and 2000.1 Thus, the finding by Teng et al. (July 31 issue)2 that patients undergoing dialysis who are treated with paricalcitol have a lower mortality rate than patients who are treated with calcitriol (18.0 percent vs. 22.3 percent per year) is more consistent with a harmful effect of calcitriol than a beneficial effect of paricalcitol. Teng et al. might have included in their analysis as true controls patients who were not treated with any form of vitamin D. Stratification according to the base-line quintiles of calcium, phosphorus, and parathyroid hormone levels would appear to be useless and might even support the incorrect conclusion that the observed differences in outcome were independent of the biochemical effects of any drug. Calcium and phosphorus levels increased more with calcitriol than with paricalcitol, so it would be important to examine the hazard ratios for death according to quintiles of calcium levels, phosphorus levels, and the product of calcium and phosphorus levels during therapy. Since follow-up laboratory tests were available, it is hard to understand why such an analysis was not performed.
2 ReferencesGiacomo Colussi, M.D.
Azienda Ospedaliera Ospedale di Circolo e Fondazione Macchi, 21100 Varese, Italy
giacomo.colussi@ospedale. varese. it 1
US Renal Data System. Excerpts from the USRDS 2002 annual data report: atlas of end-stage renal disease in the United States. Am J Kidney Dis 2003;41:Suppl 2:S29-S40
CrossRef | Web of Science2
Teng M ,Wolf M ,Lowrie E ,Ofsthun N ,Lazarus JM ,Thadhani R . Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 2003;349:446-456
Full Text | Web of Science | Medline
To the Editor:
Teng et al. did not elucidate a mechanism that would explain the superiority of paricalcitol over calcitriol for the treatment of patients undergoing long-term hemodialysis. The development and progression of secondary hyperparathyroidism promote metastatic calcification when there is an elevation of the product of the serum calcium and phosphorus levels in soft tissues, joints, blood vessels, and internal viscera, such as myocardium, lung, liver, and kidney. Vascular and cardiac calcification in particular may lead to increased mortality.1 Sprague et al. reported that paricalcitol-treated patients undergoing hemodialysis had fewer episodes of hypercalcemia than patients treated with calcitriol, as well as a higher incidence of a decreased product of the serum calcium and phosphorus levels (<50 mg2 per square deciliter).2 Among patients undergoing long-term hemodialysis, those with a calcium–phosphorus product greater than 72 mg2 per square deciliter had a risk of death that was 34 percent higher than that among patients whose calcium–phosphorus product was between 42 and 52 mg2 per square deciliter.1 It is possible that paricalcitol is more effective than calcitriol in reducing this product and mortality.
2 ReferencesYujiro Kida, M.D., Ph.D.
Tokyo Metropolitan Komagome Hospital, 113-8677 Tokyo, Japan1
Block GA ,Hulbert-Shearon TE ,Levin NW ,Port FK . Association of serum phosphorus and calcium x phosphorus product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998;31:607-617
CrossRef | Web of Science | Medline2
Sprague SM ,Llach F ,Amdahl M ,Taccetta C ,Batlle D . Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney Int 2003;63:1483-1490
CrossRef | Web of Science | Medline
To the Editor:
Although the two treatment groups in the retrospective study by Teng et al. had very similar base-line characteristics, there was a nonsignificantly higher percentage of blacks in the paricalcitol group. The superior survival among black patients who undergo dialysis has been reported previously.1 Furthermore, the paricalcitol group had higher indexes of good nutrition, such as albumin and creatinine levels. More patients in the paricalcitol group had arteriovenous fistulas for vascular access — another factor that predicts a better outcome of dialysis. Thus, the findings might be explained by the combination of minor differences that are seemingly insignificant on their own but that might add up to a difference in survival.
1 ReferencesShobha Ratnam, M.D.
Dinkar Kaw, M.D.
Panduranga Rao, M.D.
Medical College of Ohio, Toledo, OH 43614
prao@mco.edu 1
Owen WF Jr ,Chertow GM ,Lazarus JM ,Lowrie EG . Dose of hemodialysis and survival: differences by race and sex. JAMA 1998;280:1764-1768
CrossRef | Web of Science | Medline
Author/Editor Response
The purpose of our study was to compare the survival of patients undergoing hemodialysis according to the specific intravenous vitamin D analogue they received once their physicians had determined that such therapy was indicated. It is important to clarify that the mortality rates we reported (0.180 per person-year and 0.223 per person-year, respectively, in the two groups) represent an incidence density and not an absolute number of deaths per total number of patients. In contrast, the absolute mortality rates among patients who received paricalcitol and those who received calcitriol were 16 percent and 20 percent, respectively, at one year and 41 percent and 48 percent, respectively, at three years. Therefore, although we acknowledge that the difference in survival may, in part, reflect a harmful effect of calcitriol, there also appears to be a beneficial effect of paricalcitol.
Comparison with a group that was not receiving vitamin D would have required a different study design aimed specifically at addressing potential confounding by indication — that is, the possibility that factors that contribute to physicians' hesitancy to prescribe vitamin D might also be associated with decreased survival. Thus, if physicians withhold therapy from the sickest patients with the highest mortality rates, then such a study might lead to the erroneous inference that no vitamin D therapy was inferior to vitamin D therapy. While acknowledging this limitation, we agree with Dr. Colussi that such a study should be conducted.
The survival benefit was partially mitigated after adjustment for the base-line differences suggested by Ratnam et al.; however, the benefit of paricalcitol remained statistically and clinically significant. Furthermore, the results of stratified analyses (shown in Figure 2 of the article) suggested that paricalcitol had a significant benefit in 28 of the 42 multivariable-adjusted stratified models (calcitriol was favored in none). For example, we performed a multivariate comparison between black patients who received calcitriol and black patients who received paricalcitol and found that there was a survival advantage of approximately 20 percent with paricalcitol, diminishing the possibility that base-line differences in the racial balance of the treatment groups explained our results. We acknowledge that residual confounding by other nontraditional risk factors cannot be definitively ruled out.
Drs. Colussi and Kida suggest that adjustment for mineral levels measured after the initiation of therapy would be informative. However, if a drug acts through a change in laboratory values, then those laboratory values are in the causal pathway, and adjustment for them would constitute an inappropriate overadjustment.1 We therefore focused on the mineral and parathyroid hormone levels at the initiation of therapy when physicians decided which drug to prescribe. As demonstrated in Figure 3 of our article, paricalcitol was beneficial regardless of the base-line mineral and parathyroid hormone levels, suggesting that other mechanisms, in addition to altered levels of minerals, were also contributing factors.
1 ReferencesMyles Wolf, M.D.
Massachusetts General Hospital, Boston, MA 02114Ming Teng, M.D.
Fresenius Medical Care North America, Lexington, MA 02420-9192Ravi Thadhani, M.D., M.P.H.
Massachusetts General Hospital, Boston, MA 02114
thadhani.r@mgh. harvard. edu
