New Intravenous Calcimimetic Agents: New Options, New Problems. An Example on How Clinical, Economical and Ethical Considerations Affect Choice of Treatment

Background. Dialysis treatment is improving, but several long-term problems remain unsolved, including metabolic bone disease linked to chronic kidney disease (CKD-MBD). The availability of new, efficacious but expensive drugs (intravenous calcimimetic agents) poses ethical problems, especially in the setting of budget limitations. Methods. Reasons of choice, side effects, biochemical trends were discussed in a cohort of 15 patients (13% of the dialysis population) who stared treatment with intravenous calcimimetics in a single center. All patients had previously been treated with oral calcimimetic agents; dialysis efficacy was at target in 14/15; hemodiafiltration was employed in 10/15. Median Charlson Comorbidity Index was 8. The indications were discussed according to the principlist ethics (beneficience, non maleficience, justice and autonomy). Biochemical results were analyzed to support the clinical-ethical choices. Results. In the context of a strict clinical and biochemical surveillance, the lack of side effects ensured “non-maleficence”; efficacy was at least similar to oral calcimimetic agents, but tolerance was better. Autonomy was respected through a shared decision-making model; all patients appreciated the reduction of the drug burden, and most acknowledged better control of their biochemical data. The ethical conflict resides in the balance between the clinical “beneficience, non-maleficience” advantage and “justice” (economic impact of treatment, potentially in attrition with other resources, since the drug is expensive and included in the dialysis bundle). The dilemma is more relevant when a patient’s life expectancy is short (economic impact without clear clinical advantages), or when non-compliance is an issue (unclear advantage if the whole treatment is not correctly taken). Conclusions. In a context of person-centered medicine, autonomy, beneficence and non-maleficence should weight more than economic justice. While ethical discussions are not aimed at finding “the right answer” but asking “the right questions”, this example can raise awareness of the importance of including an ethical analysis in the choice of “economically relevant” drugs.


Introduction
Dialysis treatment is continuously improving, ensuring better tolerance and overall higher survival of a population that is steadily getting older and more complicated. Although the therapeutic armamentarium is now far more varied than in the past, virtually all the long-term problems related to uremia and its treatments are still unsolved: cardiovascular diseases are still the main cause of death in a context of accelerated vascular ageing; vascular access malfunction still makes it often difficult to optimize treatment; Chronic Kidney Disease related Mineral and Bone Disorder (CKD-MBD) remains one of the plagues of long-term dialysis treatment [1][2][3][4][5][6].
The focus on CKD-MBD has changed, and attention has progressively shifted from the effects it has on bones (osteopenia, pathologic fractures, reabsorptions, geodes, etc.) to its effects on the In an era of "personalized medicine", the clinical issues, influenced by economic ones, merge with ethical ones. Health technology assessment refers to the systematic evaluation of properties, effects, and/or impacts of health technology. It is a multidisciplinary process to evaluate the social, economic, organizational and ethical issues of a health intervention or health technology. Questions like "What should our treatment targets be?" or "Is it worth employing an expensive treatment in a patient with a low life expectancy?" and further "Is it logical to invest in patients with low compliance with overall treatments?" do not have univocal answers.
The present case series is therefore discussed as a means to focus attention on the interactions between the clinical, ethical and economic issues involved in the prescription of a new intravenous calcimimetic agent and underline the need for extending ethical considerations to encompass the daily choices faced in clinical practice.

Setting and Patients
The setting of the study is the Centre Hospitalier du Mans, which is presently one of the three largest non-university hospitals in France. The pool of patients on chronic hemodialysis-hemodiafiltration ranges from 95 to 110, depending on the incidence of kidney transplantation, death and transfers. In keeping with the indications of the French Society of Nephrology (Société Francophone de Néphrologie, Dialyse et Transplantation, SFNDT [42]), the population studied is a large sample of patients at high comorbidity. At the time of the study, about 70% of the patients were being treated with on-line hemodiafiltration (HDF), while the rest were being treated with conventional hemodilaysis (HD). The dialysate is acetate-free and citrate-based (calcium concentration 1.5-1.75 mmol/L; sodium 138-140 mEq/L, bicarbonate 32-36, temperature 36-37 • C; potassium: 2-3mmol/L). HDF employs high permeability membranes, with different surfaces; post-dilution HDF is employed in about half of the cases, the rest being treated with pre-dilutional HDF [43,44]. Conventional hemodialysis is performed with the same dialysate, employing medium-low permeability dialyzers. About two thirds of the patients were dialyzed with an arteriovenous fistula (AV fistula), the rest with a permanent tunnelized catheter. The dialysis policy is aimed at personalization of treatment, with incremental and more-frequent dialysis [43,44].
Dialysis efficiency was calculated using Daugirdas II Kt/V and comorbidity was assessed using the Charlson Comorbidity Index (CCI). Subjective Global Assessment (SGA) and Malnutrition Inflammation Score (MIS) were also calculated in all cases [43][44][45]. Beta-2 microglobulin was assessed 6 times per year.

Selection Criteria and Treatment Evaluation
Patients who were started on Etelcalcetide between January 2018 and January 2019 were included in the present descriptive, retrospective study, aimed at obtaining a narrative analysis of the indications and contraindications to treatment from a clinical and ethical point of view.
The indications were reviewed and discussed collegially; patients were monitored at least each 2 weeks until stabilization, and then at least monthly. Monthly tests included urea, creatinine, albumin, total proteins, Na, K, Ca, phosphorous, HCO3, at start and end of the dialysis session; vitamin D, parathyroid hormone (PTH), blood cell count, ferritin, C-reactive protein and brain natriuretic peptide. Other tests were performed with personalized frequency.
Side effects were recorded in the clinical charts, and were reviewed collegially for the present study.

Statistical Analysis
A descriptive statistical analysis was employed to describe and contextualize data with respect to our dialysis ward, and to allow comparisons with other settings. Descriptive analysis was expressed as mean ± standard deviation (SD) or median and inter-quartile range (IQR) when appropriate. Comparisons between groups were assessed by t-test for paired or unpaired data.
Trend analysis was limited to visual appreciation of the pattern observed over time; correlation between parathyroid hormone and phosphate levels was performed employing a linear model.
While an efficacy analysis is beyond the scope of the present report, dealing with a small number of heterogeneous cases, data were gathered and analyzed at different time points, before and during treatment.
For the sake of the present discussion, given the importance of costs, we considered justice as synonymous with distributive justice (the use of expensive treatments should be limited in settings with budget constraints) [48,49]. Data were discussed collegially and the conclusions were summarized narratively.

Ethical Issues
All the patients included were adults and agreed to allow use of their routine clinical and biochemical data for the sake of this study. All patients signed a written consent for analysis and publication of their data in anonymous form.
The study did not involve additional blood tests or additional imaging techniques and was approved by the hospital's ethics committee ("Avis favorable du groupe d'éthique du Centre Hospitalier du Mans du 12/06/2018").

Overall Data
Overall data on the 15 patients who started at least a period of treatment with Etelcalcetide (prevalence 13% of the current dialysis population) are summarized in Table 1. All these patients had previously been treated with oral calcimimetic agents. In all cases, the previous schedules were not able to ensure satisfactory control of PTH or hypercalcemia (see below).
At the start of treatment with intravenous calcimimetic drugs, dialysis efficacy was at target in all but one patient, who had vascular access problems; most of the patients were on HDF, with highly permeable membranes. Beta 2 microglobulin was in an acceptable range in most cases. When high, its levels were considered to be linked to a disease condition rather than to underdialysis.
Charlson Index in 5 patients was at or below 6, the limit usually employed to discriminate high comorbidity, and was above 9 in 3 (very low life expectancy).
In all patients, we observed significant variability in all measures ( Figure 1).  Table 2 summarizes the main clinical indications that were considered and balanced in the prescription of intravenous calcimimetic agents.

Overall Indications for Treatment
Insufficient efficacy of oral calcimimetic agents in PTH control was the main, and in some cases the only indication, for switching from oral to intravenous calcimimetic agents. The lack of increase in alkaline phosphatses was a controversial issue: We felt that trying to lower exceedingly high PTH levels could be of interest considering the pleiotropic effect of the hormone, as described above. The fact that lowering PTH allowed lowering phosphate levels (as described below) led us to continue the treatment, as it suggested that bone reabsorption was indeed an issue in these patients.
In only one case, the main goal was hypercalcemia, in a setting of normal, but non-suppressed PTH level; this indication was combined with nausea and low tolerance to oral calcimimetics. This patient had two reasons for being hypercalcemic: systemic tuberculosis and a small parathyroid adenoma. Calcimimetic treatment was suggested by the consultant endocrinologist on the account of the need for correcting hypercalcemia (contraindications to steroids; parathyroidectomy not accepted by the patient; unsuppressed PTH levels) in the wait for response to antitubercular treatment. Antitubercular treatment allowed correction of hypercalcemia; frank hyperparathyroidism (PTH 400-800 pg/mL) became evident and the patient is now scheduled for adenomectomy. This is the only patient who discontinued treatment, due to persistence of nausea and vomiting, in a setting of oral treatment of tuberculosis.
Tolerance is frequently a related issue, since most patients do not tolerate high doses of oral calcimimetic agents, and, interestingly, IV treatment was less associated with nausea or gastrointestinal problems, which in our series were only reported by two patients, one of whom discontinued treatment.
The second most frequent indication was poor adherence to oral calcimimetic agents. This was the only indication in three patients and was associated with nutritional problems in one further patient. Other indications and combinations are discussed in the following paragraphs (Table 2). Low compliance may offset the advantages of the drug, in particular in the presence of hyperphosphatemia.

Ethical Issues: Insufficient Efficacy with or without Low Tolerance to Oral Calcimimetic Agents
This subset of patients includes three patients with long dialysis vintage, severe CKD-MBD and dialysis-related amyloidosis, and four older patients at high comorbidity: all suffer from severe peripheral vascular disease and two have undergone toe or limb amputation.
In all these cases, the lack of side effects ensures "non-maleficence". "Autonomy", also in patients with high score comorbidity autonomy was respected through the involvement of patients according to the shared decision-making model and confirmed by and good adherence to the treatments. In this setting, the ethical issue resides in the balance between the clinical "benefit" in patients with either short life expectancy and/or well-established bone or vascular disease and "justice" (i.e., the economic impact of treatment choice). The dilemma is more relevant when a patient's life expectancy is short, as shown by a high Charlson Comorbidity Index (Table 3).

Ethical Issues: Non Compliance
Non-compliance to oral drugs was the main reason for prescribing intravenous calcimimetic agents for four patients (Table 3). For two of them, non-compliance was associated with other issues (diffuse, severe vascular disease in a young patient, and oral absorption in a severely vasculopathic patient on enteral nutrition via gastrostomy).
In these cases, non-maleficence and autonomy are not relevant, since the patients agreed to intravenous treatment, and eventually appreciated the reduced pill burden; no side effects were found, as long as calcium levels were closely monitored in the patient with borderline-low calcium levels at the start of treatment, due to non-compliance to oral calcium.
The main issue was deciding whether to employ an expensive drug to "simplify" the management of a patient who was not participating actively in his/her own treatment. Lack of compliance can make it impossible to reach the targets (calcium, phosphate) which combine with PTH to maximize benefits. Once more, the benefit of cardiovascular health is not clear in patients who are already heavily calcified, or have experienced severe cardiovascular morbidity (Broca aphasia, due to cerebral ischemia; distal amputation in the context of a diabetic foot).

Ethical Issues: Other Complex Indications
The expected advantage of reducing PTH or calcium levels in the context of hypercalcemia, in combination with mild hyper PTH and low tolerance to oral calcimimetic drugs has to be balanced with complex clinical situations, in which, for example, hypercalcemia is associated with a granulomatous disease. In these cases, treatment with an intravenous calcimimetic agent may be seen as a last-ditch attempt and considered "too expensive", given that there is no guarantee that the patient will benefit from the change.
Once more, uncertainty in the efficacy of the treatment in the long-term prognosis and costliness were the relevant issues, while non-maleficence and autonomy were not, as the patients in the study had agreed to intravenous treatment, and no side effects were found. Figure 2 reports the patterns of PTH and calcium and phosphate levels observed in patients with at least 6 months of treatment. The high variability of responses and oscillations in the biological markers is evident, and the need for strict controls has to be stressed, also for allowing identification of the treatment response (Figure 3a,b).  Overall the treatment lowered PTH levels, the exceptions being patients who started treatment in the context of hypercalcemia (Figure 4).

Discussion
Twenty-five years ago, in 1995, an editorial entitled "Who owns medical technology" appeared in The Lancet. It described the impact of new technologies on moral values, with the example of the introduction of a snowmobile in a Lapp community [50]. The new technology impacted daily life and ultimately on the moral values of a previously almost autarchic community. Technology brings more than hardware, was perhaps the obvious, but not simplistic conclusion of the paper [50].
The issue discussed here may be seen as an example of the influence of new technologies, including drug development, on the ethical framework in which clinicians work. In this regard, the case here discussed is not exceptional and may be seen as an example of the need for integrating economic and ethical issues in the routine clinical reasoning.
However, the evidence is still limited and the new drug is expensive. In fact, it is deemed so expensive that, to the best of our knowledge, for the first time in renal medicine, a reduction in price is cited as a requisite for its use in a reference guideline [32,[85][86][87][88][89].
While a commentary on the schizophrenia intrinsic in many payment systems is beyond the scope of the present discussion, we wish to note that cost differences are also determined by differences in providers: at least in many European settings, drugs linked to dialysis sessions are calculated as part of an overall reimbursement "bundle" per dialysis sessions, while oral drugs are not. Thus, cost differences between oral (not included in the hospital's budget) and intravenous (included in the hospital's budget) drugs may be perceived by the provider (hospital) as too high to be acceptable, even if the global difference is low [32,33]. This is probably necessary, but for many physicians, a quite disturbing influence by an economic aspect on a medical choice, which leads to a series of questions, that impact on prescription. In this paper, we have based our analysis of the impact of ethical issues on the clinical choice of whether or not to use a new intravenous calcimimetic agent, on the four principles of principlism [46][47][48].
The first question is efficacy (beneficence): the present PTH target range is broad, and within it, personalized targets vary depending on the importance attributed to controlling phosphate levels, which are associated with PTH levels. In patients with long life expectancy, prevention of vascular disease generally is crucial and PTH levels should probably be kept in the lower target range to minimize vascular damage. Conversely, higher PTH levels may be acceptable in very old patients and in the presence of low bone turnover, shown by low alkaline phosphate levels [23][24][25][26].
These clinical approaches raise an ethical question: in the lack of a clearly demonstrated advantage of zealous (and possibly overzealous) correction of PTH levels in our population, should physicians opt for a possibly useless (but harmless) excess of care or risk under-treatment? In other words, should we insist on correcting PTH levels in patients whose life expectancy is short or where end-organ damage (diffuse vascular calcifications or severe osteopenia) is already present?
In the absence of a sound clinical answer, the choice may follow the ethical principle of "beneficium", maximizing a potentially useful treatment versus the choice of limiting expensive therapies to patients who have a clear benefit. If we focus on benefit, our choice must be to do as much as we can for every patient, in the absence of side effects, and this is what we chose to do in our center. The answer may be different if we focus on justice, seen in economic terms; in this case, the option would be not to use the new medications to treat patients with a very low life expectancy, or established vascular and bone diseases, which are unlikely to be reversible.
Person-centered medicine could merge the two options: this approach includes a reduction in the burden of drugs and adaptations of protocols, such as relaxation of biochemical targets (i.e., more permissive hyperphosphatemia and hyperparathyroidism in patients with low life expectancy). According to this approach, autonomy (pre-eminence of the patient's values, in particular his/her quality of life), beneficence (advantages of short-term treatment), non-maleficence (burden of treatment) weight more than economic justice in leading choices [90].
Likewise, is it reasonable to use expensive treatments for patients whose low compliance may impair reaching the targets (calcium and phosphate levels), necessary for attaining the effect of the chosen treatments, or is it correct to limit their use to treating compliant patients?
Similar consideration was discussed concerning the care of obese patients and re-transplantation in subjects who had lost a previous graft due to non-adherence to treatments [91][92][93][94][95][96].
We chose to be our patients' advocate, and to try to maximize potential benefit, regardless of life expectancy, and of the presence of established cardiovascular and bone disease. Furthermore, we chose to use lower targets in patients with severe vascular disease, thus putting beneficence and non-maleficence first, with respect to justice (and economy). While we were fortunate to work in a setting in which economic considerations were not the only criteria for selecting treatments, we consider that a clear appraisal of ethical issues is a useful tool in discussing therapeutic choices.
Although efficacy was not the principal goal of our study, given the small group of patients involved and the variability of their biological data (Figures 1-4), our analysis suggests that the policy adopted was harmless, and may have improved overall control of PTH. In addition, it was at least as efficacious as the previous one, with better tolerance.
Better appraisal of benefits, possible with larger multicentric analyses, is needed to confirm the positive results, at least in terms of compliance and patients' appreciation. A close biochemical monitoring is fundamental to be able to correctly identify trends. While economic issue, national or local guidelines often limit the clinical choices, in our setting expensive choices of new drugs are allowed, but they must be motivated.
This narrative ethical analysis has the limit of being monocentric and of regarding a single drug and a small number of cases, but has the advantage of using a novel approach to the analysis of treatment choices, trying to raise physicians' and policymakers' awareness of the ethical aspects of apparently "technical " decisions.

Conclusions
The case discussed above is an example of how economic considerations have an impact on what treatment should be chosen. Would the choice between an oral or intravenous calcimimetic agent be different if their costs were equivalent? If the answer is yes, then we have to acknowledge that the cost issue, reflected in the ethical predominance of "economic" justice, is the leading principle. Conversely, a choice based on clinical issues, putting any possible advantage first, in the absence of harm, and with the patient's agreement, with respect to economic issues, represents different ethical priorities.
The aim of ethical discussions is not to find "the right answer" but instead to ask "the right questions". In this setting, we consider that this example can raise awareness of the importance of taking into account not only the clinical and economic aspects, but also the ethical ones, involved in the choice of "economically relevant" drugs. Funding: Funding none. The Centre Hospitalier Le Mans supports language correction and publication fees.

Conflicts of Interest:
Competing interests. G.B.P. received consultation fees from Amgen and Fresenius Kabi. None of the other authors has any relevant conflict of interest. Ethics approval and consent to participate. This is a retrospective analysis, based upon clinical choices independent from the study. All the patients included were adults and agreed allowing the use of their routine clinical and biochemical data for the sake of this study. All patients signed a written consent for analysis and publication of their data in anonymous form. The study did not involve additional blood tests or additional imaging techniques and was approved by the hospital's ethics committee ("Avis favorable du groupe d'éthique du Centre Hospitalier du Mans du 12/06/2018"). Consent for publication. All patients provided written consent for the anonymous use of their data. Availability of data and material. This is not a trial. The data of patients under different calcimimetic treatments are continuously updated. The datasets analysed during the current study are available from the corresponding author on reasonable request.