Cost of applying the K/DOQI guidelines for bone metabolism and disease to a cohort of chronic hemodialysis patients

original article http://www.kidney-international.org & 2007 International Society of Nephrology Cost of applying the K/DOQI guidelines for bone metabolism and disease to a cohort of chronic hemodialysis patients CA White 1, J Jaffey 2 and P Magner 2,3 1 Division of Nephrology, Department of Medicine, Queen s University, Kingston, Ontario, Canada; 2 The Ottawa Health Research Institute, Ottawa, Ontario, Canada and 3 Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada Hyperphosphatemia is a common feature of advanced chronic kidney disease (CKD) and is treated routinely with oral calcium-based phosphate binders. In 2003, the National Kidney Foundation Kidney Disease Outcomes and Quality Initiative (K/DOQI) published Clinical Practice Guidelines (CPGs) for the treatment of Bone Metabolism and Disease in CKD. These advocate broad usage of expensive non-calcium-based phosphate binders such as sevelamer. This study was designed to determine the cost of implementation of the K/DOQI CPGs as they pertain to phosphate binding in a large Canadian hemodialysis (HD) unit. Laboratory and medication data for all chronic HD patients at the Ottawa Hospital were reviewed (n ¼ 416). Patients meeting each of the relevant K/DOQI guidelines were identified. Where guidelines would recommend a switch to non-calcium binders, equivalent sevelamer doses were estimated. The cost of implementing each guideline was then calculated individually and an estimate total cost of implementing all the guidelines was derived. Overall, 53% (222) patients fulfilled at least one criterion for sevelamer use. The yearly cost of implementation of the K/DOQI guidelines at this center was estimated at $ 500 605 (American dollars). Given the significant cost, widespread adoption of the K/DOQI CPGs for Bone Metabolism and Disease should await the publication of compelling data demonstrating significant improved outcomes in patients treated with sevelamer. Kidney International (2007) 71, 312 317. doi:10.1038/sj.ki.5002037; published online 20 December 2006 KEYWORDS: clinical practice guidelines; cost; hemodialysis; hyperphosphatemia; mineral metabolism; sevelamer Correspondence: CA White, Division of Nephrology, Queen s University, Etherington Hall, Rm 3048B, 94 Stuart Street, Kingston, Ontario, Canada K7L 3V6. E-mail: cw38@post.queensu.ca Received 24 August 2006; revised 13 October 2006; accepted 24 October 2006; published online 20 December 2006 Advanced chronic kidney disease (CKD) is complicated by metabolic bone disease, hyperphosphatemia, and abnormalities of parathyroid hormone (PTH) secretion. 1 The sequelae of these include bone pain and fracture, hypertension, and extra-osseous calcification, including vascular calcification that has been implicated in the excess cardiovascular mortality of CKD patients. 2 Hyperphosphatemia itself is also associated with an increased risk of mortality. 3 Dietary phosphate (PO 4 ) restriction and oral PO 4 binders comprise the initial and principal steps in the management of hyperphosphatemia. 1 Aluminum-based PO 4 binders were once used extensively to treat hyperphosphatemia. These were largely abandoned when aluminum was found to contribute to anemia, myopathies, dementia, and lowturnover bone disease. 4 Aluminum was replaced by the calcium-based PO 4 binders, calcium acetate, and calcium carbonate (CaCO 3 ). There is now growing concern that these may contribute to or accelerate the vascular calcification observed in hemodialysis (HD) patients. 1,5 9 More recently, non-calcium and non-aluminum-based binders such as sevelamer have been developed. As yet, there are no published randomized controlled trials (RCTs) comparing sevelamer to calcium-based phosphate binders with clinical endpoints such as cardiovascular events and mortality. In 2003, the US National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K-DOQI) published Clinical Practice Guidelines (CPGs) for Bone Metabolism and Disease in CKD. These CPGs advocate the use of sevelamer across a range of common clinical scenarios in CKD (Table 1). Sevelamer is significantly more costly than the calcium-based salts. By analyzing patients in our large HD program, we have determined the economic impact of a common sense application of the phosphate-binding recommendations of the NKF K/DOQI CPGs for Bone Metabolism and Disease in CKD. RESULTS In December 2003, there were 470 patients receiving chronic HD at the Ottawa Hospital or at one of its affiliated satellite units. Fifty-four were excluded (28 for sevelamer use, 10 for multiple missing lab values, and 16 for acute hospitalizations 312 Kidney International (2007) 71, 312 317

CA White et al.: Sevelamer economic analysis o r i g i n a l a r t i c l e Table 1 The K/DOQI CPGs for bone metabolism and disease in CKD that suggest sevelamer use in HD patients Guideline and level of evidence Guideline summary Criteria for patient identification 5.5 Opinion Dose of elemental Ca should be less then 1.5 g/d. Identify patients with elemental Ca dose greater than 1.5 g/d. 5.6 Evidence Ca-based binders should not be used if plasma ipth is less Identify patients with a plasma ipth less than 16.5 pmol/l who than 16.5 pmol/l on two consecutive measures. 5.6 Evidence Ca-based binders should not be used if serum Ca greater than 2.54 mmol/l. 13c Opinion Decrease or eliminate Ca-based binders and vitamin D if plasma ipth is less than 11 pmol/l. are not on vitamin D. Identify patients with a serum Ca greater than 2.54 mmol/l and a serum PO 4 greater than 1.78 mmol/l who are not on vitamin D or patients with serum Ca greater than 2.54 mmol/l who are on less than 1.5 g/d of elemental Ca and who are not on vitamin D or patients with serum Ca greater than 2.54 mmol/l with a plasma ipth greater than 33 pmol/l. Identify patients with a plasma ipth less than 11 pmol/l who are not on vitamin D. Ca, calcium; CKD, chronic kidney disease; CPG, clinical practice guideline; d, day; HD, hemodialysis; ipth, intact parathyroid hormone; K/DOQI, Kidney Disease Outcomes Quality Initiative; PO 4, phosphate. Table 2 Characteristics of the HD cohort (n=416) Age (yrs) 68717 Male gender (%) 250 (60) Number at satellite HD unit (%) 239 (57) Serum Ca (mmol/l) a 2.470.2 Serum PO 4 (mmol/l) b 1.670.5 Plasma ipth (pmol/l) c 31.2738.4 Number taking calcitriol (%) 234 (56) Number taking CaCO 3 (%) 350 (83) Mean daily elemental Ca dose (g) d 1.570.9 Number with 0.4 g/d or greater difference between medication 131 (31) database and patient reported elemental Ca dose (%) Number with serum Ca less than 2.37 mmol/l (%) e 221 (53) Number with serum PO 4 less than 1.78 mmol/l (%) e 314 (75) Number with plasma ipth between 16.5 33.0 pmol/l (%) e 103 (25) Ca, calcium; CaCO 3, calcium carbonate; d, day; HD, hemodialysis; ipth, intact parathyroid hormone; PO 4, phosphate; yrs, years. a Mean corrected serum Ca values (October, November, and December). b Mean serum PO 4 values (October, November, and December). c Mean of two most recent ipth values. d Mean dose of those taking CaCO 3. e Based on December values. or previous parathyroidectomy) leaving the final cohort of 416 patients who were included in the analysis. The biochemical results and medication use of the cohort are shown in Table 2. On average, calcium and phosphate control were within K/DOQI targets. 1 Average intact PTH (ipth) was slightly above recommended target of 16.5 33 pmol/l. 1 In December, only 53 and 75% of patients met the K/DOQI calcium and phosphate targets and only 25% were within ipth targets. 1 Fifty-six percent were prescribed calcitriol. The majority of patients (84%) were prescribed CaCO 3 as a phosphate binder. There was a greater than 400 mg of elemental calcium/day discrepancy between the medication database and the self-reported CaCO 3 dose in 31% of patients. Table 3 shows the number of patients who fulfilled the K/DOQI guideline criteria for sevelamer and the economic impact of calcium substitution with sevelamer. A total of 222 (53%) patients met at least one the K/DOQI requirements for substitution of CaCO 3 with sevelamer. The most common indication for sevelamer (133 patients, 32%) was a dose of elemental calcium greater than 1.5 g/day (guideline 5.5). In comparison, only 36 patients (9%) qualified owing to hypercalcemia (guideline 5.6) and 79 patients (19 %) qualified for two successive ipth values below 16.5 mmol/l (guideline 5.6). Of the relevant guidelines, only guideline 5.6 was labeled evidence based by the K/DOQI work group. Conversion of all calcium above 1.5 g/day to sevelamer would cost on average an extra $4.93 per patient per day or $239 230 yearly for the cohort. The cost of substitution for hypercalcemic patients was estimated at $88 936 yearly for the cohort. The total estimated yearly cost for guideline adherence was $500 605. The results are only slightly different using the prescribed dose of calcium instead of the self-reported dose. The criteria for sevelamer use was met by 231 patients with an associated cost of $6.28 per patient per day or $529 522 yearly for the cohort. DISCUSSION This study reveals the significant cost associated with the application of the NKF K/DOQI CPGs for Bone Metabolism and Disease in CKD in a single Canadian HD program. This expense is in addition to the already high cost of maintaining this cohort on HD estimated at $19 123 227 yearly. 10 Assuming the mineral metabolism parameters of the patients enrolled in this study are similar to those of other Canadian HD populations, the yearly cost of guideline adherence for Canada s 13 620 HD patients 11 would exceed 16 million dollars. Thirty-three percent of this patient cohort qualified for sevelamer use based on ingestion of calcium exceeding 1.5 g/ day (guideline 5.5). This translates to a cost of $239 230 yearly for the cohort. The rationale for choosing 1.5 g/day as the calcium threshold is not well explained in the NKF K/ DOQI CPGs and it is difficult to extrapolate from the available literature what constitutes a safe dose of calcium. Evidence supporting a detrimental effect of calcium ingestion first emerged from observational studies linking calcium salt ingestion to radiographic evidence of extra-osseous calcification. 6,7,11 The Treat to Goal study randomized 200 prevalent Kidney International (2007) 71, 312 317 313

o r i g i n a l a r t i c l e CA White et al.: Sevelamer economic analysis Table 3 Number of patients meeting the K/DOQI CPGs for bone metabolism and disease in CKD and estimated cost of guideline adherence Guideline and level of evidence Guideline summary Number of patients (%) Extra cost of sevelamer a (US$/day/patient) Extra cost of sevelamer a (US$/year/cohort) 5.5 Opinion Elemental Ca greater than 1.5 g/d 133 (32%) 4.93 239 230 5.6 Evidence Plasma ipth less than 16.5 pmol/l 79 (19%) 7.90 227 802 on two consecutive measures 5.6 Evidence Serum Ca greater than 2.54 mmol/l 36 (9%) 6.77 88 936 13c Opinion Plasma ipth less than 11 pmol/l 95 (23%) 7.75 268 866 Any of above 222 (53%) 6.18 500 605 Ca, calcium; CKD, chronic kidney disease; CPG, clinical practice guideline; ipth, intact parathyroid hormone; K/DOQI, Kidney Disease Outcomes Quality Initiative. a Calculated by subtracting the cost of CaCO 3 from the cost of the substituting sevelamer. HD patients to sevelamer or to calcium salts. 5 Those on sevelamer had significantly lower median percent change in coronary artery (6 vs 25%) and aortic (5 vs 28%) calcification scores as measured by electron beam computed tomography at 1 year. Similar results in another smaller RCT have been reported. 9 The relationship between calcification scores and clinical cardiovascular disease or mortality in HD patients has not been well established. One small observational study demonstrates a nonsignificant association between a coronary artery calcification score by electron beam computed tomography of greater than 200 and death in 104 chronic HD patients. 12 On multivariate analysis, the coronary artery calcification score was only marginally demonstrated to be an independent predictor of death with a relative risk of 1.001 (1.000 1.002). 12 It should be acknowledged that K/DOQI accords an opinion label to guideline 5.5 and, in its accompanying discussion, recommends that cost, amongst other things, be taken into account by the clinician. Preliminary results of the Dialysis Clinical Outcomes Revisited study have been reported in abstract form (J Am Soc Nephrol; 281(A): 2006). In this RCT of 2100 HD patients, patients were assigned to receive sevelamer or calcium salts and were followed for 3 years. The major clinical end points were death and cardiovascular events. Preliminary results do not show a significant reduction in mortality or cardiovascular events in those treated with sevelamer. Some benefit was reported in subgroups: patients over 65 years old had a 22% risk reduction in all cause mortality (P ¼ 0.03); patients who were still alive and who continued therapy for more than 2 years, had a 34% reduction in all cause mortality (P ¼ 0.02). The absence of published data documenting any benefit of sevelamer on clinical end points precludes a formal economic analysis. However, a simpler cost trade-off analysis does permit an estimatation of the clinical impact required for sevelamer to achieve cost effectiveness. The cost in US dollars of a myocardial infarction, stroke, coronary artery bypass graft surgery, and peripheral angioplasty/surgery for non-hd patients in Canada has been estimated at $4913, $11 977, $10 763 and $3571, respectively. 13 Thus, in our cohort of 416 patients, every year sevelamer would need to prevent either 102 myocardial infarctions, 42 strokes, 47 coronary artery bypass graft surgeries, 140 peripheral revascularizations or some combination of these in order to be cost neutral. It is difficult to envision any therapy in HD patients able to achieve this degree of benefit. In fact, these numbers vastly exceed the cohort s expected event rate. Based on the results of a large RCT in HD patients with clinical cardiovascular end points, we would anticipate only 29 strokes and 21 coronary artery bypass graft surgeries in this cohort over a 3-year period. 14 Calcium avoidance in HD patients in the face of widespread vascular calcification and cardiovascular disease seems intuitive. However, vascular disease in CKD is highly complex with multiple putative contributors. 15 Traditional cardiovascular disease risk factors such as diabetes, hypertension, and dyslipidemia are highly prevalent in the CKD population. 15 In addition to abnormal mineral metabolism, a number of other CKD-specific risk factors such as inflammation, oxidative stress, proteinuria, and uremic toxins are also postulated to play a role. 15,16 As a result, it is plausible that a single intervention such as calcium avoidance would have no significant effect on cardiovascular outcomes in the HD population. The preliminary results of the Dialysis Clinical Outcomes Revisited trial (J Am Soc Nephrol; 281(A): 2006) appear to support this notion. One could postulate that the increased cost associated with sevelamer use may be partially offset by the reduced need for 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors therapy. HD patients have a high prevalence of dyslipidemia. 17 In the Treat to Goal study, sevelamer significantly reduced the total cholesterol, the low-density lipoprotein cholesterol and the non-high-density lipoprotein cholesterol levels. 5 However, The 4D ( Deutsche Diabetes Dialyse Studie) a large RCT with clinical cardiovascular outcomes, did not show a benefit of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in diabetic HD patients. 14 Even before the publication of the 4D study, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors were uncommonly used in HD patients, 14,18 20 perhaps reflecting the low prevalence of significantly elevated low-density lipoprotein levels in this population 17 and the inverse relationship between cholesterol levels and mortality in end-stage renal disease. 21 One can reasonably postulate that utilization rates will only decrease following the publication of 314 Kidney International (2007) 71, 312 317

CA White et al.: Sevelamer economic analysis o r i g i n a l a r t i c l e 4D. For these reasons, the cost impact of improved lipid profile with sevelamer would likely be minimal. There are certain instances in which it is reasonable, perhaps even desirable, to prescribe sevelamer. For example a hypercalcemic hyperphosphatemic patient may indeed benefit from avoidance of calcium containing phosphate binders as set out in guideline 5.6. Other circumstances in which sevelamer may be beneficial include patients with calcific uremic arteriolopathy (guideline 5.7). Manns et al. 22 have also examined the economic impact of broadly applying the K/DOQI CPGs for Bone Metabolism and Disease recommendations, and have published results with similar conclusion to ours. In their Canadian cohort of 499 dialysis patients, 51% met at least one guideline, whereas in their American cohort 64% fulfilled at least one guideline. Using the average dose of sevelamer required to achieve phosphate control in the Treat to Goal study, 5 they report an estimated yearly cost of $3644 US per patient. We have estimated a much lower cost of $1203 US per patient. This present study differs significantly in the way estimated sevelamer doses were derived. We generated a conversion algorithm tailored to each particular guideline and we also applied each patient s actual calcium dose to establish the appropriate equivalent sevelamer dose. We felt this strategy would provide a more accurate estimation of sevelamer requirements, which is reflected in this study s lower projected cost of guideline adherence. In addition, we attempted to model a real world approach to mineral metabolism abnormalities (Table 1). Patients meeting the K/DOQI criteria for sevelamer use were not included if there were other reasonable strategies to attain the recommended targets. For example, patients who were hypercalcemic but who had PO 4 values within target were not included as a simple dose reduction of calcium could potentially restore their biochemistry to within acceptable ranges. We also sought to determine as accurately as possible the actual ingested calcium dose for each patient by conducting patient interviews. Interestingly, we found significant discrepancies between patient-reported doses and database doses (Table 2). Other strengths of this study include the inclusion of the both in-hospital and satellite unit HD patients ensuring that both healthy and sick HD patients were represented. In addition, the medication data was retrieved 2 months following the publication of the guidelines. This timeliness ensures that there would be little change in practice patterns by the attending nephrologists resulting from their familiarity with the specifics of the guidelines. The low sevelamer utilization rate (26 patients) confirms the lack of adoption of the guidelines at the time of the analysis. Weaknesses of this study should be noted. Firstly, this analysis is very conservative. It did not take into account adequacy of control of plasma PO 4. Twenty-five percent of the cohort had PO 4 levels above the recommended target. Also, patients for whom there was no documented verbal dose of calcium were considered to not be taking any. Together, these would lead to an underestimation of sevelamer requirements and cost. Secondly, the cohort only included patients on HD. Cost of guideline adherence for patients on peritoneal dialysis can therefore not be estimated. Thirdly, this was a single center study, which could limit its external validity. Finally, this study provides only a snap shot of mineral metabolism control over a period of 3 months. A patient may meet a guideline criterion 1 month and not the next. The impact of this on our results is difficult to predict. There is currently no international body overseeing the process by which CPGs are developed. In the United Kingdom, the National Institute for Clinical Evidence has established guidelines for CPG development. 23 The Ontario Government Ministry of Health in partnership with the Ontario Medical Association uses an instrument called the Appraisal of Guidelines Research and Evaluation to review published guidelines. 24 Both National Institute for Clinical Evidence and Appraisal of Guidelines Research and Evaluation incorporate economic impact as a critical step in guideline assessment. K/DOQI does not incorporate financial considerations in their guideline development. Whether or not economics should be guiding principle in CPG development is an ongoing source of discussion. 22,25 29 This issue will become increasingly important as other expensive therapies developed specifically for patients with CKD and abnormal mineral metabolism, such as lanthanum carbonate and cinecalcet, become more widely available. This study demonstrates the substantial cost of adherence to the K/DOQI CPGs for Bone Metabolism and Disease in CKD as they pertain to phosphate binders in HD patients. Evidence supporting the relative benefit of sevelamer over calcium salts is preliminary and modest in scale. This is reflected in the opinion label allotted to several of relevant K/DOQI guidelines. The Canadian Society of Nephrology has also recently published guidelines addressing oral phosphate binders. 30 These conclude that there is insufficient evidence to recommend the use of any one particular phosphate binder and caution that sevelamer is more expensive but not superior at controlling serum phosphate levels. Until further evidence emerges clearly documenting the clinical benefit of any one phosphate binder, clinicans should consider both economics and individual patient characteristics when selecting a phosphate binder. MATERIALS AND METHODS Study population All patients receiving thrice weekly HD at the Ottawa Hospital or one of its affiliated satellite units for at least 3 months by December 2003 were included. Patients were excluded if they were hospitalized for an acute illness at the time of data collection, had undergone a parathyroidectomy, were already prescribed sevelamer, or had multiple data points missing. The Ottawa Hospital dialysis unit and its satellites use a computerized database system to record patient medications and clinical information. On the day of the December 2003 monthly blood tests, patient s medication data, as recorded in the medication list section of the database, was abstracted. On the same day, the renal unit nurses asked all HD patients or their caregivers the formulation and dose of phosphate Kidney International (2007) 71, 312 317 315

o r i g i n a l a r t i c l e CA White et al.: Sevelamer economic analysis Table 4 Algorithm for conversion of CaCO 3 to sevelamer Guideline Guideline summary Dose conversion 5.5 Elemental Ca greater than 1.5 g/d Replace Ca dose above 1.5 g/d with sevelamer 5.6 Plasma ipth greater than 16.5 pmol/l on two consecutive measures Replace entire Ca dose with sevelamer 5.6 Serum Ca greater than 2.54 mmol/l Replace entire Ca dose with sevelamer 13c Plasma ipth less than 11 pmol/l Replace entire Ca dose with sevelamer Ca, calcium; CaCO 3, calcium carbonate; d, day; ipth, intact parathyroid hormone. binders they were taking. This was recorded in narrative form in the computerized data base progress notes. This additional step was included to enhance accuracy of the medication data. Laboratory data The results of the October, November, and December 2003 monthly blood work (total calcium (Ca), phosphate (PO 4 ) and albumin) were recorded. All ipth levels measured in 2003 were also recorded. Calcium levels were corrected using the formula c(ca) ¼ t (Ca) þ 0.02(40 (albumin)) as recommended by K/DOQI. 1 ipth was measured using the DiaSorin assay, which has a coefficient of variation of 10%. Albumin was measured by the TinaQuant assay, which has a coefficient of variation of 8%. Phosphate and calcium were measured using the Auto chem. assay, which has a coefficient of variation of 2%. Analysis The NKF K/DOQI CPGs for Bone Metabolism and Disease in CKD 1 were reviewed and the relevant guidelines were selected for inclusion (Table 1). Each guideline s status as either Opinion or Evidence based was noted. Patients were identified who fulfilled the guideline conditions that would dictate treatment with sevalamer. The three consecutive monthly serum calcium and phosphate values were analyzed separately. As vitamin D therapy can contribute to PTH suppression, only patients not prescribed vitamin D were included in the analysis of guidelines 5.6 (iptho16.5 pmol/l) and 13c. Similarly, as CaCO 3 and vitamin D can lead to hypercalcemia, only hypercalcemic patients who were hyperphosphatemic (PO 4 41.8 mmol/l) or who were taking less than 1.5 g of elemental calcium per day and who were not prescribed vitamin D were included in the analysis of guideline 5.6 (Ca42.54 mmol/l). The analysis of guideline 5.6 (Ca42.54 mmol/l) also included any hypercalcemic patients with an ipth above the recommended target of 16.5 30 pmol/l regardless of whether they were on vitamin D. These patients require vitamin D to control their hyperparathyroidism. Discontinuing it in order to control calcium levels is therefore not a viable long-term option. The number of patients fulfilling the K/DOQI guidelines for sevelamer by individual guideline and the total number of patients fulfilling at least one of the guidelines were determined. The selfreported dose of CaCO 3 taken by patients meeting each guideline was noted and used for the subsequent analysis. Patients for whom either no dose or non-compliance was recorded by the nursing staff were assumed to not be taking calcium. An algorithm for substitution of CaCO 3 by sevelamer was developed to reflect the guideline recommendations (Table 4). The dose of sevelamer required to replace the CaCO 3 was then calculated for each patient. Dose equivalency between elemental calcium and sevelamer (1 g elemental calcium ¼ 4.16 g of sevelamer) was derived from the Treat To Goal Study, the largest published randomized study comparing sevelamer to calcium-based binders (1). The cost of replacing CaCO 3 with sevelamer was then established. The cost of sevelamer ($1.498/800 mg) and CaCO 3 (TUMs regular 500 mg, $0.0174/100 mg elemental calcium including 40% markup, 7% government sales tax and 8% provincial sales tax) was obtained from the McKesson, Canada wholesale pricing guide. 31 Dispensing fees were not included. The cost of substitution was calculated by subtracting the cost of the CaCO 3 from the cost of the replacement sevelamer. All costs are reported in American (US) dollars. Costs in Canadian (Cnd) dollars were converted to US dollars based on the Bank of Canada s nominal noon exchange rates on 1 Dec 2003 (1Cnd$ ¼ 0.77 US$). 32 The final cost of guideline adherence was estimated as follows: the cost of CaCO 3 replacement by sevelamer was calculated for all patients meeting guideline 5.6 (iptho16.5 pmol/l 2)). For the remaining patients (all those not meeting guideline 5.6 (iptho16.5 pmol/l 2), those who met guideline 13c were identified and the cost of replacing their CaCO 3 by sevelamer was tabulated. A similar calculation was then carried out for the remaining patients (all those not meeting guidelines 13c or 5.6 (iptho16.5 2)) who met guideline 5.6 (Ca42.54 mmol/l). Finally the analysis was repeated for those only meeting guideline 5.5. 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