Assessing the effect of oral activated vitamin D on overall survival in hemodialysis patients: a landmark analysis

Cardiovascular disease is an important cause of death in patients with chronic kidney disease (CKD) [1, 2]. Apart from diabetes, dyslipidemia, and atherosclerosis, non-traditional risk factors, especially secondary hyperparathyroidism, vascular calcification, and heart failure, all play important roles in patients with CKD and end stage renal disease (ESRD) [3‐6]. In addition, vitamin D insufficiency and deficiency, which result from malnutrition, reduced 1α-hydroxylase activity, and increased fibroblast growth factor-23, are highly prevalent in advanced CKD and contribute to secondary hyperparathyroidism and adverse cardiovascular outcomes [7].

In the literature, low 25-hydroxyvitamin D and 1, 25-dihydroxyvitamin D levels are associated with increased all-cause and cardiovascular mortality in the general population, CKD, and uremic patients [8‐14]. Pleiotropic effects of activated vitamin D include improving endothelial function, inhibition of vascular smooth muscle proliferation and vascular calcification, suppression of renin production, and modification of inflammatory response [15‐18]. Treatment with activated vitamin D is associated with lower incidence of left ventricular hypertrophy, myocardial fibrosis, and pulmonary congestion [17, 19, 20].

Findings from observational studies have suggested that administration of activated vitamin D was associated with reduced mortality and improved cardiovascular outcome in advanced CKD and ESRD patients [21‐25]. Results from one study had ever suggested that patients treated with oral activated vitamin D had a 45% reduction in mortality but the survival benefit was inversely related to the vitamin D dose [22]. Findings from another meta-analysis of randomized controlled trials had suggested that treatment of vitamin D compounds was associated with increased risk of hypercalcemia and hyperphosphatemia while inconsistently reducing parathyroid hormone (PTH) levels. The potential beneficial effect on mortality was unproven and underpowered to be evaluated because only few studies reported clinical hard outcomes [26].

In clinical practice, concerns about hypercalcemia and potential vascular calcification have confined treatment of vitamin D in patients with elevated PTH and with relatively low calcium levels. Besides, patients prescribed vitamin D are generally younger and healthier, implying unmeasured confounders that could not be removed by statistical adjustment, which could have biased the findings from previous studies [22, 27, 28].

In Taiwan, the prevalence of ESRD reached 2584 per million in 2010, while rates of 2260 and 1870 were reported in Japan and the United States [29]. Given the potential benefits of activated vitamin D mentioned above, we hypothesized that prescription of activated vitamin D should improve overall outcome in ESRD patients. Regarding the universal coverage of health care and bundled payment for dialysis in Taiwan, the National Health Insurance Research Database (NHIRD) can be employed to examine the effect of activated vitamin D in the real world setting and establish the domestic evidence for clinical practice.

Using NHIRD, we aimed to determine the prevalence of activated vitamin D prescriptions, including calcitriol and alfacalcidol, in incident hemodialysis patients in Taiwan and the association of vitamin D use with potential effect on all-cause mortality.

Between Jan 1, 2001 and June 30, 2009, there were 83,433 incident uremic patients who had undergone hemodialysis treatment for more than 90 days. After exclusion of those who were not eligible for CIC (n = 21,380) either due to renal function recovery or non-continuation of dialysis therapy, those registered “dead” but with missing death date (n = 350), and those with date of vitamin D prescription later than the last recorded date of dialysis therapy (n = 218), a total of 61,485 patients were included (Fig. 1). Patients who were not eligible for CIC were healthier and had fewer comorbidities (data not shown).

Of these 61,485 patients, 15,793 (25.7%) patients had ever been prescribed oral activated vitamin D during the follow-up period. The median duration of vitamin D use were 354 days (IQR 89–973 days). Among these patients, 8867 (56.1%) received vitamin D in the first 360 days after hemodialysis initiation (Additional file 1: Table S1).

Patients who died (n = 5757) or had follow-up less than 360 days (n = 2971) were excluded from analysis (Fig. 1). Vitamin D users (n = 8151) were significantly younger and healthier than non-users (n = 44,606), with less prevalence of diabetes and accompanying past histories of myocardial infarction or stroke. Vitamin D users also had more prevalent use of arteriovenous fistula and less use of graft or permanent catheters as long-term vascular access (Table 1).

By the end of the follow-up from the landmark time (median 1019, IQR 473–1777 days), there were 2619 deaths during 29,158.6 person-years of observation (crude mortality rate 8.98 per 100 person-years) among vitamin D users, as compared with 18,482 deaths during 142,948.7 person-years follow-up (12.93 per 100 person-years) among non-users (Additional file 1: Table S2). The survival curve of activated vitamin D users and non-users was shown (Fig. 2). Vitamin D users were less likely to die compared to non-users in unadjusted (HR 0.69 [95% CI, 0.66–0.72]) and multivariate adjusted model (HR 0.91 [95% CI, 0.87–0.95]) (Table 2).

After propensity score method employed and matching, the baseline covariates were balanced between vitamin D users and non-users (Table 1). The overlap of the distribution of propensity score across vitamin D users and non-users were displayed, before and after PS matching (Additional file 1: Figures S1 and S2), respectively. Vitamin D users still had a lower risk of death with the method of PS trimming (HR 0.71 [95% CI, 0.68–0.74]), IPTW (HR 0.94 [95% CI, 0.92–0.96]), and PS matching (HR 0.94 [95% CI, 0.90–0.98]) (Table 2). We had further performed a matched pairs analysis from which vitamin D users still had a lower risk of death (HR 0.91 [95% CI, 0.86–0.96]), compared with non-users.

To evaluate prescribing pattern and examine the dose response relationship, ambulatory claims for activated vitamin D prescriptions were collected in the first 360 days after hemodialysis initiation. Using 0.25 μg as dosage unit, the median (IQR) cumulative dosage were 80 (35–168), 60 (30–112) and 60 (30–112) units in three 120-day intervals, respectively (Additional file 1: Table S3).

In the trajectory analysis (Additional file 1: Appendix S4), 326 (6.2%) patients were noted to have been given higher than average doses, while the remaining 6849 (93.8%) were prescribed the conventional daily dosage (Fig. 3). Whether high dose or conventional dose vitamin D users, they were prescribed higher dose in the first 120 days. After adjustments of potential confounders, we observed a significant survival benefit in patients receiving conventional dose (HR 0.88 [95% CI, 0.84–0.92]) and high dose activated vitamin D (HR 0.66 [95% CI, 0.55–0.78]) (Table 3). Compared with conventional dosage group, the high dose group still had a lower risk of death (HR 0.75 [95% CI, 0.63–0.89]).

We did sensitivity analyses by analyzing patients who had regular hemodialysis in hospital-based dialysis units. The activated vitamin D users (n = 5449) were still younger (58.7 versus 62.1 years) and had fewer baseline comorbidities than non-users (n = 23,245). The crude mortality rate was lower in vitamin D users compared with non-users (8.60 versus 12.36 per 100 person-years) (Additional file 1: Table S2). After adjustment for age, sex, vascular access type, comorbidities, medications, urbanization, and hospital levels, vitamin D users were still associated with a lower risk of death (HR 0.91 [95% CI, 0.87–0.96]). Using PS matching, vitamin D users still had a lower risk of death (HR 0.95 [95% CI, 0.89–1.00]) (Table 4).

Additionally, we compared 6848 vitamin D users with 50,921 non-users, using the 180th day after hemodialysis initiation as the landmark time. Vitamin D users were noted to have a lower risk of death in the multivariate adjusted (HR 0.87 [95% CI, 0.84–0.91]) and PS matched model (HR 0.94 [95% CI, 0.90–0.98]), compared with non-users. After trajectory analysis and adjustment of potential confounders, high-dose vitamin D users still had a lower risk of death, compared with non-users (HR 0.64 [95% CI, 0.55–0.74]) and conventional dose users (HR 0.76 [95% CI, 0.65–0.89]), respectively.

In this cohort of 61,485 incident hemodialysis patients between 2001 and 2010, patients treated with oral activated vitamin D in the first 360 days after dialysis initiation had a survival advantage compared with those not treated, even after adjustment for potential confounders. The result was significant in the entire cohort using a different landmark time and subgroup of hospital-based hemodialysis patients. The presence of dose-response relationship further supported the potential benefit of activated vitamin D prescription in these patients.

According to the Dialysis Outcomes and Practice Pattern Study (DOPPS), intravenous vitamin D was most common in the United States but oral administration was more prevalent in all other countries. The percentage of patients on vitamin D were 33% in France, 66% in the United States, and 39% in Japan in the DOPPS III (2005–2006) [27]. In the Current Management of Secondary hyperparathyroidism – a multicenter Observational Study (COSMOS), 48% of prevalent hemodialysis patients in Europe were using activated vitamin D, mostly calcitriol and alfacalcidol [45].

In Taiwan, oral route but not intravenous administration of activated vitamin D is reimbursed by the NHI. In our study, we found that only 25.7% of patients had ever been prescribed activated vitamin D, exclusively in oral form. The prescription of activated vitamin D in Taiwan was not as prevalent or as early as those in the United States and European countries [24, 27, 45]. This may result from the different indications between vitamin D supplementation and suppression of parathyroid hyperplasia [46]. Higher geographic latitude or dark skin may be associated with a higher prevalence of vitamin D deficiency, higher PTH levels, and more prescriptions of activated vitamin D [47]. In Taiwan, the widespread use of inexpensive calcium-containing phosphate binders may lead to reduced PTH levels, which contributed to fewer prescriptions of vitamin D. In addition, the level of vitamin D was rarely tested in ESRD patients in Taiwan and activated vitamin D was often prescribed for secondary hyperparathyroidism, which often developed in the later dialysis vintage. The median time to the first prescription was 252 (IQR 31–919) days after hemodialysis initiation, obviously later than that in the DOPPS, although the exact indications and levels of PTH were not available from the NHIRD.

In the literature, oral calcitriol use was associated with lower all-cause mortality in CKD stage 3–4 patients. In these non-dialyzed CKD studies, patients given calcitriol were older, having higher PTH level and lower glomerular filtration rate, and more were diabetics [21, 23]. In contrast, evidence from observational studies of hemodialysis patients have shown that patients prescribed activated vitamin D were younger and healthier [22, 24]. Different from the above studies, our study did not choose time-dependent exposure to assess vitamin D effect because the concept of time-dependent has been thought of as more focused on the “state of exposure” on the outcome rather than the effect of early vitamin D supplement or exposure on the long-term outcome. We also did not use marginal structural model (MSM) to deal with time-varying covariates because of lack of laboratory data and detailed comorbidity information in claims data of hemodialysis treatment in the NHI. Instead, we retrieved not only diagnostic codes but comprehensive medication use and vascular access type obtained from claims data of all medical services during baseline periods, which were deemed reliable for input in PS to adjust for imbalance between vitamin D users versus non-users.

Survival benefits of oral calcitriol have been found, in those receiving mean daily doses of less than 1 μg [22]. However, the author also found that the lower the vitamin D dose, the lower the risk of death. Using MSM, Miller et al. [48]. have found that higher dose paricalcitol was associated with greater survival in hemodialysis patients but failed to confirm this using conventional Cox model or PS matched method. However, patients taking paricalcitol represented a small proportion of the hemodialysis population in the U.S., and thus, the result could not be extrapolated to populations in other countries [48]. Concerning the high cost, paricalcitol is not reimbursed in the NHI and thus rarely used in Taiwan practically.

Randomized controlled trials comparing activated vitamin D use versus placebo are unacceptable ethically. Thus, observational studies still have a role in leading the trend of clinical practice.

The strength of this study is the large real-life cohort with detailed information of comorbidities and co-medications and a long follow-up duration up to 10 years. In addition, the inclusion of incident hemodialysis patients with utilization of landmark design reduced immortal time bias [49]. Although the design of landmark analysis introduced misclassification bias when some vitamin D users were categorized into non-users, as may underestimate the effect of vitamin D, the true beneficial effect must be even greater since we found a lower risk of mortality in vitamin D users. Despite lack of active comparators, we adopted PS matching and reduced the imbalance between users and non-users.

Additionally, our study had illustrated trajectories of vitamin D prescription dosage and to highlighted the temporal changes in the first 360 days of dialysis initiation. It is straightforward to use trajectories to classify different dosage groups which may help us to determine the dose exposure patterns. The positive association of higher dose calcitriol or alfacalcidol and reduced all-cause mortality in our analysis further supported the beneficial effect of activated vitamin D in hemodialysis patients. Reducing use of calcium-based phosphate binders should be considered to trade off for more activated vitamin D prescriptions to avoid the risk of hypercalcemia, inadequately suppressed PTH levels, or low bone turnover disease. Further study may be needed.

One major limitation of our study is that there were no laboratory data such as calcium, phosphorus, PTH, hemoglobin, smoking status, and markers of inflammatory status available from Taiwan NHI medical claims.

We conducted a stratified analysis in only female patients to minimize the potential confounding by smoking since the prevalence of smoking is very low (4.3%) among female population in Taiwan [50]. Compared with non-users, vitamin D users were associated with a lower all-cause mortality risk (HR 0.89 [95% CI, 0.84–0.94]) in females who were largely non-smokers. Such reduced effect observed in females was also similarly observed in male patients (HR 0.93 [95% CI, 0.87–0.98]), who had a smoking prevalence of 46.8%. This sex-stratified analyses provided further reassurance that the potential of confounding by smoking is very small in our study.

The overall mortality in this hemodialysis cohort in Taiwan was substantially lower than that in other countries, as may result from different race, life style, or fewer cardiovascular events and better medical accessibility due to comprehensive health insurance coverage [30, 51]. The observation from our study implies that using inexpensive activated vitamin D may bring about significant survival benefit, even though newer vitamin D analogs with fewer hypercalcemic side effects were not prescribed extensively in Taiwan.

In incident hemodialysis patients, treatment of oral calcitriol or alfacalcidol was associated with lower risks of death. There was no excess risk for death in patients receiving higher doses of vitamin D. Therefore, our data supports the prescription of activated vitamin D in these patients unless contraindicated.