Secondary hyperparathyroidism (sHPT) occurs early in chronic kidney disease (CKD) and is a major component of the CKD-related mineral and bone disorder (CKD-MBD).1 Major CKD-MBD complications include fractures, cardiovascular disease (CVD), and mortality.2⿿7

Control of serum calcium, phosphorus and PTH has been associated with reduced mortality risk in haemodialysis patients,8 hence effective sHPT control is important in these patients. Reduced persistence, compliance, and/or adherence with oral medications are a common problem, especially in CKD patients,9 with non-adherence rates of 3⿿80% reported.10⿿12 Non-adherence was associated with increased mortality in the dialysis population,13 highlighting a potential unmet need among patients who do not persist with sHPT therapies. Clinical trial data,14 where persistence-corrected analyses revealed more beneficial effects associated with cinacalcet (Sensipar®/Mimpara®) prescribing than uncorrected analyses, support this hypothesis.

The current study, conducted in European patients initiating haemodialysis (HD) treatment, aimed to describe separately the characteristics of patients who initiated long-term sHPT therapies with either prescribed activated vitamin D sterols (AVDs) or cinacalcet, the conditions and reasons for non-persistence and the consequences of initiation and non-persistence, respectively, for the control of serum biochemistry parameters.

In this large European haemodialysis patient cohort, more patients initiated ⿿ as evidenced by prescriptions ⿿ calcitriol-alfa than paricalcitol, with fewest cinacalcet initiations observed. Major geographical prescribing practice differences were observed, reflecting drug reimbursement policies and the availability/application of national and international guidelines. Physician and centre habits might also influence the observed baseline differences in sHPT treatment, with sHPT severity and serum calcium in particular dictating prescribing patterns. High PTH, phosphorus and, to a lesser extent, calcium were drivers for cinacalcet prescription in approved countries.

The observed PTH reductions with the AVDs might be mediated in part by associated increases in serum calcium. The increases in serum calcium with paricalcitol accord with previous observational research18 but not clinical trial data19,20; the stricter inclusion/exclusion criteria employed in the RCTs might explain the discrepancy. The reduction in all three parameters among cinacalcet initiators is consistent with previous research.21⿿24

Whilst reasonably good real-life control of serum iPTH levels was achieved in most treated patients in this study, this was not the case for control of serum calcium and phosphate, which was more often outside KDOQI target ranges (and to some extent also outside KDIGO ranges) in AVD-treated patients. The less favourable pre-treatment control in the cinacalcet group than in the AVDs groups was probably due to the secondary introduction of cinacalcet in those patients resistant to AVDs treatment. Attainment of all three mineral metabolism targets was poor, even with treatment. This is a near-universal observation, reflecting the real-life challenges in this regard, where correcting one parameter often represents a trade-off against control of another.

Whilst post-initiation laboratory trajectories have been described previously, as outlined above, this is possibly the first study to describe in detail non-persistence to sHPT treatments and the evolution of laboratory parameters post-discontinuation. The greater observed persistence to cinacalcet compared to AVDs might relate to clinician preference or the lack of a suitable alternative in patients uncontrolled on AVDs treatment alone. Laboratory biochemistry post-discontinuation largely mirrored that observed for initiation and differed by treatment modality: whilst iPTH increased for all three treatment groups, calcium and phosphate decreased for calcitriol-alfa and paricalcitol patients and increased for cinacalcet patients. When an alternative prescription-coverage threshold definition for discontinuation was applied, non-persistence rates increased for all three treatment groups and laboratory trajectories were more conservative. We hypothesise that our main definition may represent definitive treatment drop-outs which occur infrequently, whilst our sensitivity definition captures treatment adaptations which occur more frequently.

Drug discontinuation may be patient- or physician-led and it was impossible to determine in this study which were patient decisions, based on drug intolerance or pill fatigue, and which were medical decisions based on overcorrection of PTH levels (all treatment groups), undesirable increases in calcium and phosphate levels (mostly with AVDs) or undesirable decreases in calcium levels (with cinacalcet). Discontinuation may also be driven by laboratory goal-attainment, suggesting that some clinicians do not view sHPT as a long-term chronic disorder requiring continuous therapy. Most initial paricalcitol prescriptions were administered intravenously, affording a greater clinical influence on treatment decisions for this group. Nevertheless, the pattern of paricalcitol non-persistence (main definition) was no different from the exclusively oral calcitriol-alfa group, suggesting that, for AVDs at least, treatment discontinuation was mainly clinician-led.

Other methodological aspects require consideration. This study utilised data from a single private dialysis provider, hence findings might partially reflect internal policies, limiting generalizability. We assume 100% persistence/non-persistence when this is unlikely. Patients could contribute to each treatment sub-population and/or be on multiple therapies at once and this is not captured/reflected, increasing the potential for confounding. Accordingly, these results could be considered within the framework of ⿿assessing the effect of the initial intention of a single treatment (or its withdrawal)⿿. Our 45-day rule for discontinuation, whilst internally consistent within AROii, is arbitrary and other time periods might have been more appropriate (others have advocated for data-driven definitions based on prescription length25). Our descriptive analytical approach, where statistical modelling was not utilised, does not take into consideration characteristics (observed or otherwise) which could confound the relationship between patients⿿ biochemistry and treatment initiation/discontinuation and could explain, to an extent, the clinical differences observed between the treatment groups. Similarly, we focused on total treatment populations when sub-group analyses might have been more revealing. For example, the different prescribing pattern in the Iberian Peninsula ⿿ especially with regard to cinacalcet ⿿ might provide insights into biochemical control which could inform healthcare decision-making by clinicians, policy makers, payers, etc., but this was beyond the scope of the study. Finally, we reported but did not impute missing data which may be important if, for example, less frequent iPTH measurement is indicative of poorer clinical care which in turn is reflected in poorer control of calcium and/or phosphorus.

In conclusion, sHPT biochemistry parameters dictated treatment initiation and discontinuation within the confines of differing geographical treatment patterns. Clinicians appear to adhere to treatment guidelines, although goal achievement is poor. In real-life conditions, better biological control of sHPT appears to be more easily achievable with cinacalcet than with AVDs, where iPTH response might be mediated in part by serum calcium.

The ARO CKD Research Initiative is a joint observational research commitment from Amgen and Fresenius Medical Care, fully funded by Amgen (Europe) GmbH, Zug, Switzerland.

The sponsors were responsible for data collection (FMC) and data management (FMC, Amgen), provided resources for statistical and epidemiological analysis, and participated in the interpretation of data and preparation of the manuscript (Amgen).

Every step of development of the project, from design and scientific conduct of the study, through interpretation of the data, to preparation, review, and approval of the manuscript, was led by authors who are also members of the ARO Steering Committee. Results and their interpretations were discussed by all members of the ARO Steering Committee at plenary meetings twice a year.

A.L. de F. reports having received Advisor/Consultant fees from Amgen, Fresenius; speaker fees from Abbott, Amgen and Fresenius.

J.F. reports having received Advisor/Consultant fees from Abbott, Amgen, Chugai, Genzyme and Vifor; speaker fees from Abbott, Amgen, FMC, Genzyme and Mitsubishi.

F.K. reports having received Advisor/Consultant fees from Amgen. T.B.D. reports having received Advisor/Consultant fees from Abbott, Amgen, Baxter, FMC, Genzyme, KAI Pharmaceuticals, Kirin, Theraclion, and Vifor; speaker fees from Abbott, Amgen, Chugai, Genzyme, Kirin, and Vifor; and grant/research support from Amgen, Baxter, and Shire.

D.C.W. reports having received research funding from Abbott, Genzyme and AstraZeneca, honoraria from Amgen, Abbott, Fresenius, Janssen, Otsuka, Shire and Vifor.

I.G. is a contractor for Amgen. I.A.G. and M.F. are full-time employees of Amgen who may own stock and/or stock options in Amgen. D.M. is a full-time employee of Fresenius Medical Care.