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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

44th European Renal Association/European Dialysis and Transplant Association Annual Congress

Barcelona, Spain / June 21-24, 2007

It has been well documented that approximately one-third of patients with any chronic condition do not take their medication as prescribed. According to Dr. Rob Horne, Director, Centre for Behavioural Medicine, The School of Pharmacy, University of London, UK, non-adherence is not always a character trait. Rather, it is a behaviour that varies over time and across treatment intervals and is rooted in a pre-existing set of beliefs all individuals hold concerning illness and its treatment. Non-adherence can be unintentional; a patient may sincerely wish to take their medication but simply cannot because the procedure is too complex or physically difficult to follow.

Conversely, non-adherence can often be intentional—“Patients deliberately decide to take either no medication or, more commonly, take less than instructed,” Dr. Horne observed. Thus, for every patient about to embark on a medical regimen, there is a “unique mixture” of both practical and perceptual barriers that will dictate whether or not they will be adherent to a regimen. “And until we understand what those barriers are and deal with them, our interventions are likely to be ineffective,” Dr Horne told the audience.

Necessity and Concern: Results from the BMQ

Behind the thinking that determines the degree to which patients will be adherent are “necessity beliefs”—what patients believe their personal need is to take a medication to maintain or improve current and future health—and concerns about immediate and long-term side effects.

Study findings across a wide range of illnesses and treatment strategies including dialysis reveal a pattern in the way patients balance their concerns about taking any medication against their need for it—the “necessity-concerns framework,” as Dr. Horne characterized it, a useful model by which to assess how likely patients will be adherent.

In a pilot study carried out by Dr. Horne and colleagues, this necessity-concerns framework was used to identify the various types of non-adherent behaviour among dialysis patients and their prevalence.

Results obtained on the validated Beliefs About Medicines Questionnaire (BMQ) developed by Dr. Horne were compelling. Among 221 dialysis participants, 41% said they would forget to take their phosphate binder; 38% said they would forget to take them at mealtimes; 23% altered the dose; 21% took less than instructed; and 19% deliberately decided to miss a dose.

Asked if respondents disagreed with statements such as “Without this medicine, I would be very ill,” over half disagreed with it; 39% doubted their future health relied on a phosphate binder; 35% doubted it was essential to take their phosphate binder on time; over 30% did not understand why they needed to take a phosphate binder to begin with; and 32% expressed doubts about the efficacy of a phosphate binder to control phosphate levels.

Forty per cent worried about the long-term effects of the medication; 32% indicated it was inconvenient to take the tablets; and 30% indicated that the number of tablets they had to take was a problem. Patients with low adherence as determined by the BMQ were also shown to believe significantly less in their personal need for a phosphate binder and had much higher concerns about the potential toxicity of these agents than patients who were deemed to be highly adherent.

As Dr. Horne observed, judging the relative value of taking a phosphate binder is difficult for patients, because taking it as prescribed does not make them feel immediately better and missing a dose does not make them feel immediately worse. In some instances, high phosphate levels in the blood may result in pruritus for some patients. Otherwise, he noted, there are very few short-term consequences for non-adherence to a phosphate binder regimen. Nevertheless, he stressed, physicians need to ensure that the solution they are recommending—in this case, treatment with a phosphate binder—reflects a patient’s understanding of the problem.

“What matters is the degree to which the patient endorses their personal need for treatment,” indicated Dr. Horne. “We need to identify the practical and perceptual barriers that influence a patient’s ability to take their medication and their motivation to do so, then address those barriers and tailor convenient regimens for them to follow.”

Exploring the Options

Simplifying a regimen may not be the only solution towards improving adherence but it can be helpful, especially given the onerous pill burden dialysis patients face.

In a study carried out by Dr. Rajnish Mehrotra, Associate Professor of Medicine, David Geffen School of Medicine, University of California at Los Angeles, and Los Angeles Biomedical Research Institute, Torrance, the median daily tablet burden for a patient with chronic kidney disease (CKD) was 17, with a range from seven pills a day to 45—“and over half of this tablet burden is from the phosphate binders,” indicated Dr. Mehrotra.

Lowering the dosing frequency of phosphate binders might help reduce that tablet burden; however, this strategy has not proven to be successful and patients are still compelled to take phosphate binders with every meal.

Since it became available in the US in early 2005, lanthanum carbonate has been prescribed for over 76,000 patients. Studies have shown that this non-calcium-containing phosphate binder controls phosphate levels effectively and is well tolerated, with no evidence of long-term safety risks over a treatment interval of up to six years. As Dr. Mehrotra observed, “One of the biggest strengths of the drug lies in its low tablet burden.”

He cited a large European study in which he collaborated which consisted of 366 patients with stage V CKD already on phosphate binder therapy who were switched to lanthanum carbonate. Prior to the switch, almost 40% of the group were taking two or more phosphate binders, as Dr. Mehrotra noted. Twelve weeks after being switched to lanthanum carbonate, the mean level of serum phosphate achieved was 1.84 mmol/L.

He reported, “Whether patients were on one phosphate binder or two at baseline, the levels achieved were almost identical, so it didn’t matter how many phosphate binders patients were taking at baseline. If we switched them to lanthanum carbonate, it was possible for many of these patients to remain on a single phosphate binder.”

Moreover, 77% of the cohort achieved target serum phosphate levels on lanthanum carbonate 3000 mg/day, “and this dose can be achieved with one tablet per meal,” he told listeners. The maximum dose of lanthanum carbonate is 4500 mg/day, or two tablets with each meal.

In another large US-based study evaluating patient and physician preference for the non-calcium-containing phosphate binder, patients were again treated to a serum phosphate target of 1.13 to 1.78 mmol/L with an initial dose of 3000 mg for four weeks. The dose was then titrated to 4500 mg/day until target levels were achieved. About half of the group was on sevelamer at baseline and about one-third were on a calcium-based binder. Patient satisfaction with the regimen was assessed at baseline and periodically up to week 24 of therapy.

Some 60% of patients indicated they were satisfied with their previous therapy at baseline, as Dr. Mehrotra indicated. However, this rose to over 80% at week 24 and the greatest improvement in satisfaction was noted in the reduction of the number of tablets patients had to take (Table 1). Physicians also preferred their patients being on lanthanum carbonate, Dr. Mehrotra reported, adding that because of its low tablet burden, “lanthanum carbonate may help overcome one practical barrier to adherence and result in some improvement in adherence to therapy.”

Table 1. Overall Patient and Physician Satisfaction

Calcium Burden of Dialysis Patients: COSMOS Findings

Getting patients on dialysis to comply with their phosphate binder therapy is central to overall serum phosphate control but other issues, including calcium burden, remain. Calcium-based binders including calcium acetate and calcium carbonate are widely used and they help control phosphate levels, as evidence attests. On the other hand, there is growing evidence indicating that elevated total body calcium load—which is increased with the use of calcium-based phosphate binders—may raise the risk of cardiovascular morbidity and mortality.

COSMOS (Current Management of Secondary Hyperparathyroidism: A Multi-Centre Observational Study) is an open prospective cohort study in which clinical parameters and outcome data are being analyzed in 5700 hemodialysis patients.

In a preliminary analysis presented here, lead author Dr. José L. Fernández-Martín, Hospital Universitario Central de Asturias, Oviedo, Spain, and colleagues reported that at 12 months, patients who met Kidney Disease Outcomes Quality Initiative (K/DOQI) targets for calcium had a lower overall mortality of 8.9% compared to 11.4% for those who did not, as well as lower hospitalization rates (35.9%) than patients outside the targets (39.8%). The same analysis also showed that cardiovascular mortality rates were lower in patients within calcium targets at 3.9% vs. 6.1% for those outside the targets.

In previous analyses of lanthanum carbonate and calcium-based phosphate binders, investigators noted major differences in episodes of hypercalcemia between those on the non-calcium-based phosphate binder and those taking calcium. It is also known that when patients surpass the K/DOQI limits for serum calcium—which many do in order to reach K/DOQI targets for serum phosphorus—there is a risk of contributing to vascular calcification.

As a non-calcium-based phosphate binder, sevelamer represents an attractive option but it is still associated with a large pill burden. For example, in an analysis of lanthanum carbonate and sevelamer, the mean daily dose for patients taking lanthanum carbonate was 3618 mg vs. 7357 mg for sevelamer for equal levels of serum phosphate control. These doses translated into a mean daily tablet burden of 3.6 tablets/day for patients on lanthanum carbonate vs. 9.2 tablets/day for those on sevelamer. Investigators concluded that the reduced tablet burden achievable with the new high-strength formulation of lanthanum carbonate might have positive implications for patient adherence.

It has also been established that renal osteodystrophy, the bone pathology associated with CKD, continues to be a significant problem in dialysis patients and, through extraskeletal calcification, is linked to an increased risk of cardiovascular mortality.

In the largest prospective series of bone biopsies ever carried out, investigators examined the risk of renal osteodystrophy in over 400 bone biopsies in three different studies evaluating lanthanum carbonate. Patients in all three studies were randomly selected to undergo bone biopsies so they were representative of the population of hemodialysis patients treated with lanthanum carbonate, as investigators emphasized. Bone biopsy results in the first study showed no major shift in bone balance for patients on either lanthanum carbonate or those on calcium carbonate at the end of one year.

In the second study, there was similarly very little change in activation frequency at the end of two years in patients treated with either lanthanum carbonate or standard phosphate binder therapy and only two patients developed a mineralization defect at study end point. Again, bone balance was basically maintained at the two-year mark in both treatment groups. In the third study, which included an open-label extension out to four to five years, bone biopsy values at five years were consistent with those seen after one year and no patient has yet to develop a mineralization defect with long-term lanthanum carbonate therapy.

Investigators concluded that there is no evidence to indicate that lanthanum carbonate has adverse effects on bone, at least not after four to five years of treatment, indicating a difference from the toxicity profile for aluminum-based phosphate binder therapy which adversely affects bone.

Summary

Among the many challenges in the management of CKD patients, high phosphate and calcium levels are key as they have serious implications for outcome. Avoiding calcium-based phosphate binders can reduce overall calcium burden for dialysis patients but sevelamer, a non-calcium-based phosphate binder, is still associated with a high pill burden. Reducing that pill burden is possible with lanthanum carbonate and as a non-calcium-containing phosphate binder, it should not contribute to vascular calcification and overall calcium-attributable cardiovascular risk. Moreover, the treatment is cost-effective in patients who exceed K/DOQI guidelines for serum calcium levels.

Questions and Answers

This question-and-answer session was conducted with Dr. Rajnish Mehrotra, Associate Professor of Medicine, David Geffen School of Medicine, University of California at Los Angeles, and Los Angeles Biomedical Research Institute, Torrance, during the scientific sessions.

Q: Results from an audience poll suggested that efficacy, not patient preference, is a driving factor in phosphate binder choice. Please comment.

A: Efficacy of a drug is clearly important, but no matter how effective a drug is, if a patient is not going to take it, it isn’t going to be effective. So patient preference is important for adherence.

Q: Has the use of lanthanum carbonate increased the proportion of patients who can achieve target serum phosphate levels?

A: Anecdotally, I would say that putting patients on lanthanum carbonate has increased the proportion of patients who achieve target levels, although we have not systematically analyzed this. But based on the European study, clearly patients who were on a previous phosphate binder had a lowering of their mean serum phosphate levels when they were switched to lanthanum carbonate, so it is possible more patients are closer to target levels when switched. The greatest challenge is to achieve a sustained reduction in serum phosphorus—to keep levels within range month to month, year after year. If you look at the proportion of patients who achieve sustained target phosphate levels, it falls to less than 10%. So CKD is a chronic disease with a lot of comorbidities and a high tablet burden, all of which results in problems with sustained control of serum phosphorus.