PERSPECTIVE
The EVOLVE study is negative, so what does this ‘bitter pill’ of disappointment mean now for renal patients?
EVOLVE cinacalcet use
For the non-nephrologist, it would be very legitimate to ask why should anyone have come to the conclusion that by manipulating serum PTH concentrations in CKD there might be a patient-level survival advantage? Of course, with extreme elevation of serum PTH concentrations, such as are seen in CKD patients with severe secondary or tertiary hyperparathyroidism, hypertension, dyslipidaemia, anaemia, skeletal problems, cardiovascular and other ectopic calcifications are all well recognised, and, likely do impact adversely on overall survival. Furthermore, there are many cross-sectional associations between different bone metabolism parameters in CKD (3,4) and outcomes; these include serum phosphate, calcium, PTH, vitamin D and FGF-23 concentrations (4,5). Of note, from the epidemiological point of view there are significant differences between the different analyses in terms of their relationship to patient survival: plasma phosphate has the strongest, graded, relationship between serum concentrations and outcomes, whereas in many studies, there is a ‘U’ shaped relationship for serum PTH concentrations (5–7). The drug cinacalcet, the first clinically available allosteric agonist of the cell-surface calcium-sensing receptor – a ‘calcimimetic’ approved for treatment of SHPT (8) – has a marked ability to suppress both serum calcium and PTH concentrations in CKD (and a rather smaller potential to decrease plasma phosphate concentrations). Much effort over more than two decades has been applied to trying to combat the increased
286
cardiovascular mortality of CKD; these efforts have included altering dialysis ‘dose’, dialysis type/membrane, clearances of uraemic middle molecules, concentrations of haemoglobin, cholesterol, homocysteine, type of oral phosphate binder, and the use of antioxidant therapy (2). Using cinacalet (8,9) can potentially help address the association between elevated PTH, calcium and phosphate concentrations with adverse outcomes, as cinacalcet acts on all three of these simultaneously (at least in short-term administration studies). Cinacalcet use in some countries is limited by national guidelines (e.g.: in UK influenced by the HTA/NICE guidance 10) or by a comprehensive capitation reimbursement system (e.g. Romania, Hungary, Portugal), in marked contrast with much more liberal use of this expensive new therapy in many Southern European countries.
The extremely high morbidity and mortality experienced by subjects with chronic kidney disease (CKD) has often been described and reviewed (1), but this familiarity should not breed indifference to the huge burden of premature cardiovascular disease – something which becomes more obvious, but increasingly challenging to treat, as GFR declines, or proteinuria increases (1,2). The health outcomes for a middle-aged person entering renal replacement therapy are as bad as those seen with a major solidorgan malignancy; while there has been modest progress in improving outcomes over the last two decades, the diagnosis of significant or progressive CKD should and thus still does continue to cast a shadow over patients, carers and healthcare professionals alike.
The EVOLVE study The EVOLVE study was a multicentre, prospective, randomised, placebo-controlled trial in which the use of cinacalcet vs. placebo was assessed in 3883 adults undergoing dialysis (9). All the patients were eligible to receive conventional therapy, including phosphate binders, vitamin D compounds or both. Randomisation was stratified according to country and diabetes status with the use of fixed blocks. The sponsor, investigators and patients were unaware of the treatment assignments (9). After randomisation, patients received either cinacalcet or placebo at a starting dose of 30 mg daily, thereafter the dose was titrated against serum PTH concentration Dialysis, phosphate binders, vitamin D sterols, calcium supplements and other medications were prescribed at the discretion of the treating physicians, who were encouraged to adhere to published clinical-practice guidelines [which changed significantly during the trial itself (11)]. The primary composite end-point was the time to death or the first non-fatal cardiovascular event (myocardial infarction, hospitalisation for unstable angina, heart failure or a peripheral vascular event).
ª 2014 John Wiley & Sons Ltd Int J Clin Pract, March 2014, 68, 3, 286–289. doi: 10.1111/ijcp.12261
Perspective
Secondary end-points included the time to the individual components of the primary composite endpoint, death from cardiovascular causes, stroke, bone fracture and parathyroidectomy (9,12). The proposed sample size was based on the following assumptions: an annual rate of the primary composite end-point of 23.2% in the placebo group, a 20% treatment effect, a 1.5-year enrolment period, a 4-year total study duration, an annual rate of loss to follow-up of 1%, an annual rate of drop out (withdrawal from active treatment before a primary event) of 10% in the cinacalcet group and a rate of drop-in (use of commercially available cinacalcet before a primary event) of 10% in the placebo group. After it became apparent that the overall (blinded) event rate was well below 20.8%, the trial duration was then extended by 16 months to allow for accrual of the requisite number of events. In the 3883 subjects who were randomised from 22 countries, including the USA, Canada, Australia, three Latin American nations, Russia and 15 European nations, the burden of overt cardiovascular disease at baseline was high (e.g. myocardial infarction 12.4%, heart failure 23.3%). The median plasma parathyroid hormone concentration at baseline was 692 pg/mL (10%, 90% range, 363–1694 pg/ml). At baseline, 87.2% of subjects were prescribed phosphate binders and 57.5% were prescribed active vitamin D compounds. Demographic data, comorbid conditions and baseline laboratory data varied significantly across regions (10,12). The daily median cinacalcet dose was 55 mg (10th–90th percentile, 28–130 mg) for cinacalcet and 125 mg (10th–90th percentile, 43–161 mg) for placebo. A total of 80.0% of patients in the placebo group reached the maximum daily dose, as compared with 38.3% of those in the cinacalcet group. Figure 2 from the original publication shows the cumulative incidence of discontinuation of the study drug. Using the original assumption of a 20% treatment effect, but with the observed study duration and observed rates of events, drop out and drop-in rates, which were assumed to be constant, the statistical power was re-estimated to be only 54% (from the previous 90%). The primary composite end-point was reached in 938 of 1948 patients (48.2%) in the cinacalcet group, as compared with 952 of 1935 patients (49.2%) in the placebo group. So, this was a negative outcome study (10). Put another way, in an unadjusted intention-to-treat analysis, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe biochemical secondary hyperparathyroidism who were undergoing dialysis. Yet, the reason for this was not lack ª 2014 John Wiley & Sons Ltd Int J Clin Pract, March 2014, 68, 3, 286–289
of biochemical efficacy of the primary intervention, as the two groups were clearly separated by the marked impact of cinacalcet on serum PTH and calcium concentrations, maintained over a long duration. The effect of cinacalcet was definitely more pronounced among older patients (p = 0.03 for interaction). It seemed to be more evidently effective in those with PTH concentrations < 900 pg/ml (which seems counter-intuitive if the hypothesis being tested is essentially the ‘toxicity’ of elevated calcium and PTH). Hypocalcaemia developed in seven times as many patients in the cinacalcet group as in the placebo group, and nausea and vomiting were twice as common with cinacalcet. Adverse effects led to discontinuation of the study drug in 18.1% of patients in the cinacalcet group and 13.0% of those in the placebo group. Rates of serious adverse events were similar in the two groups.
Analysis and context So, another large and expensive (for CKD) study, lasting around 6 years, was duly undertaken, but this yielded nothing ‘practice changing’ at the end of all of that worthy effort. Why not, we might legitimately ask? There are quite a large number of observations that need to be made about this trial. First, and the only one given in praise, is recognition of the huge effort and determination involved to mount a study in a complex group of patients such as those on dialysis. That is, however, the point where the praise ceases, and from now one, there is criticism and censure. Let us re-examine the trial substrate – subjects on haemodialysis. The median age was around 55, and the median time on dialysis prior to enrolment into the trial was 45 months (10–90% 8.5– 190 months). The median age for starting dialysis in the USA and UK is around 65–70 years, and the first year’s mortality post dialysis commencement is significantly higher than the 3 years that follow (13). So, clearly, a younger cohort with a survival ‘advantage’ was the main subject material of the trial, which itself would render any trial outcomes difficult to extrapolate, as would the issues around side effects, and discontinuations. This might explain the lower than predicted overall event rates, and thus the need to extend the trial duration to await the collection of enough events to permit sufficient statistical power. Moreover, it is very clear that the younger subjects in the trial failed to yield sufficient events compared with the older subjects; indeed, age remains much the most potent factor in determining outcomes on dialysis. The forest plot for the interaction of outcome with age clearly shows that any
287
288
Perspective
‘traction’ on outcomes that could be obtained by the use of cinacalcet was only seen in those aged over 60 years, and, curiously, in those with PTH concentrations < 900 pg/ml. We believe that this element of trial design was a serious misjudgement – allowing subjects aged from 18 to 80 to be enrolled – with a mild biochemical abnormality in many cases – this study would have been possible to conduct much faster, and possibly with a different outcome, had the age range been 50–80 years and the serum PTH concentration inclusion range more relevant. The additional time this study took to complete allowed an ever greater number of people to drop out, and most importantly, to drop-in, to the study – the rate at which patients on placebo ended up taking cinacalcet was (at around 27%) a very major concern and must be seen as a profound disappointment; much more effort should have been undertaken by the trial sponsors to prevent this from happening. Equally, up to 40% of placebo patients did not receive vitamin D therapy, and around 15% of patients did not receive oral phosphate binders (9). The use of calcimimetics without concurrent use of vitamin D therapy is neither typical nor sufficiently explored by other trials to be recommendable for clinical use. Not only was this ‘age/risk homogenisation’ a consequence of the trial design, but the composite endpoint was too broad and unfocussed. This is relevant as the primary entry criterion was a simple elevation of plasma PTH concentration (to within a range of 300–800 pg/ml). Elevation of plasma PTH concentration at this level has negligible effects on outcomes and survival, does not constitute a ‘condition’ (and in particular it does not constitute hyperparathyroidism except in a very narrow, biochemical, sense) and thus is not precise enough biologically to be a major selection criterion for trial inclusion. The relatively normal bone turnover markers, including bone-specific alkaline phosphatase, and the lack of impact of the use of cinacalcet on any bone-related outcome (e.g. fracture), tellingly make this point. In our view, a very significant proportion of the subjects enrolled into this study did not have a condition that could reasonably have warranted the use of the drug being studied! This implies that in the investigators’ minds diseases can be defined purely biochemically, which is regrettable. Another very telling statistic about the ‘mildness’ of any hyperparathyroidism seen in this EVOLVE study is that unlike the registration studies for cinacalcet reported in aggregate in 2005, where the median cinacalcet dose was 93 mg/day (14), in the EVOLVE study the median dose was around 55 mg. Even with this lower dose employed, the prevalence of nausea and vomiting was significant on
active treatment, and it will be interesting to see if any quality of life domains were helpfully influenced; our prediction is that this will prove to be negative too. Not long after the full publication of EVOLVE there was a Cochrane review of the use of cinacalcet in nephrology. Cochrane and Embase databases (through 7 February 2013) were electronically searched to identify randomised trials evaluating effects of calcimimetic therapy on mortality and adverse events in adults with CKD (15). Two independent reviewers identified trials, extracted data, and assessed risk of bias. Eighteen trials comprising 7446 participants compared cinacalcet plus conventional therapy with placebo or no treatment plus conventional therapy in adults with CKD. In moderate- to high-quality evidence in adults with CKD stage 5D (dialysis), cinacalcet had little or no effect on all-cause mortality [relative risk, 0.97 (95% confidence interval, 0.89–1.05)], had imprecise effect on cardiovascular mortality [0.67 (0.16–2.87)], and prevented parathyroidectomy [0.49 (0.40–0.59)] and hypercalcaemia [0.23 (0.05–0.97)], but increased hypocalcaemia [6.98 (5.10–9.53)], nausea [2.02 (1.45–2.81)] and vomiting [1.97 (1.73-2.24)]. On average, treating 1000 people with CKD stage 5D for 1 year had no effect on survival and prevented about three patients from experiencing parathyroidectomy (PTX), whilst 60 experienced hypocalcaemia and 150 experienced nausea. These effects would be challenging indeed for a drug as cheap as aspirin. Cinacalcet is somewhat more costly than that per patient year administation (currently around $250,000,000 per annum cost in the USA).
Conclusions Cinacalcet reduces the need for PTX in patients with CKD stage 5D, although, as there was local flexibility about what constituted suitable grounds for surgical PTX intervention, this statement needs to be carefully qualified. If the decision to proceed to were exclusively related with the degree of serum PTH concentration elevation, without symptoms, this would be a most different set of patients to those undergoing PTX for bone pain, myopathy and fractures. Cinacalcet use in this population seemed to have no impact on CV or total mortality despite sustained impact on the ‘biochemical risk’ for adverse outcomes. Where does this leave ‘CKD-MBD’ as a clinical concept? In our view, the lack of impact on hard outcomes by significant manipulation of serum PTH and calcium concentrations seriously questions the CKD-MBD concept, and even some of the KDIGO ª 2014 John Wiley & Sons Ltd Int J Clin Pract, March 2014, 68, 3, 286–289
Perspective
CKD-MBD biochemical ‘targets’ proposed in 2009 (11). Nephrology research directions now urgently need to be refocussed around key questions, which if answered, might impact patient outcomes substantially and meaningfully. Is it possible to slow the CKD progression and attenuate comorbidities? Can replacement with fixed doses of compounds known to be deficient in CKD, ever lead to improved outcomes? Will it be possible to fund such studies, given that some of the simple, sometimes complementary, therapies offer little financial return for industry – the traditional funder of first, or last, resort for nephrology (16)? Should we not now concentrate on nested care ‘bundles’ of interventions in one well-conducted study, and by so doing, grasp the opportunity to show that we can actually influence patient-level (as opposed to biochemical) outcomes positively? After all, diabetologists have shown us that this style and type of trial in a
References 1 Hajhosseiny R, Khavandi K, Goldsmith DJ. Cardiovascular disease in chronic kidney disease: untying the Gordian knot. Int J Clin Pract 2013; 67: 14–31. 2 Covic A, Gusbeth-Tatomir P, Goldsmith D. Negative outcome studies in end-stage renal disease: how dark are the storm clouds? Nephrol Dial Transplant 2008; 23: 56–61. 3 Fernandez-Martın JL, Carrero JJ, Benedik M et al. COSMOS: the dialysis scenario of CKD-MBD in Europe. Nephrol Dial Transplant 2013. 4 Cannata-Andıa JB, Fernandez-Martın JL, Locatelli F et al. Use of phosphate-binding agents is associated with a lower risk of mortality. Kidney Int 2013. doi: 10.1038/ki.2013.185. 5 Garrett G, Sardiwal S, Lamb EJ, Goldsmith DJ. PTH–a particularly tricky hormone: why measure it at all in kidney patients? Clin J Am Soc Nephrol 2013; 8: 299–312. 6 Mazzaferro S, Goldsmith D, Larsson TE, Massy ZA, Cozzolino M. Vitamin D metabolites and/or analogs: which D for which patient? Curr Vasc Pharmacol 2013.
ª 2014 John Wiley & Sons Ltd Int J Clin Pract, March 2014, 68, 3, 286–289
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complex population can be undertaken (17). Do we need in addition to embrace complementary and different methodologies and issues that need to be addressed to design studies to address key questions? We think the answer to all of these questions is ‘yes, we do’!
Disclosure None. 1
D. Goldsmith,1 A. Covic2 Nephrology, Guy’s Hospital, King’s Health Partners, London, UK 2 Renal Department, Parhon Hospital, Iasi, Romania
Correspondence to: David Goldsmith, Nephrology, Guy’s Hospital, King’s Health Partners, London, UK Tel.: 02071887188 Fax: 02071885646 Email: [email protected]
7 Sardiwal S, Magnusson P, Goldsmith DJ, Lamb EJ. Bone alkaline phosphatase in CKD-mineral bone disorder. Am J Kidney Dis 2013. 8 Verheyen N, Pilz S, Eller K et al. Cinacalcet hydrochloride for the treatment of hyperparathyroidism. Expert Opin Pharmacother 2013; 14: 793–806. 9 EVOLVE Trial Investigators, Chertow GM, Block GA et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012; 367: 2482–94. 10 NICE guidance. http://guidance.nice.org.uk/TA117/ ReviewProposal (accessed July 2013). 11 Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl 2009; 113: S1–130. 12 Chertow GM, Correa-Rotter R, Block GA et al. Baseline characteristics of subjects enrolled in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial. Nephrol Dial Transplant 2012; 27: 2872–9.
13 Steinman TI. The older patient with end-stage renal disease: is chronic dialysis the best option? Semin Dial 2012; 25: 602–5. 14 Cunningham J, Danese M, Olson K, Klassen P, Chertow GM. Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism. Kidney Int 2005; 68: 1793–800. 15 Palmer SC, Nistor I, Craig JC et al. Cinacalcet in patients with chronic kidney disease: a cumulative meta-analysis of randomized controlled trials. PLoS Med 2013; 10: e1001436. doi: 10.1371/journal. pmed.1001436. 16 Levin A, Lancashire W, Fassett RG. Targets, trends, excesses, and deficiencies: refocusing clinical investigation to improve patient outcomes. Kidney Int 2013; 83: 1001–9. 17 Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358: 580–91.
Paper received July 2013, accepted July 2013
The EVOLVE study is negative, so what does this ‘bitter pill’ of disappointment mean now for renal patients?
EVOLVE cinacalcet use
For the non-nephrologist, it would be very legitimate to ask why should anyone have come to the conclusion that by manipulating serum PTH concentrations in CKD there might be a patient-level survival advantage? Of course, with extreme elevation of serum PTH concentrations, such as are seen in CKD patients with severe secondary or tertiary hyperparathyroidism, hypertension, dyslipidaemia, anaemia, skeletal problems, cardiovascular and other ectopic calcifications are all well recognised, and, likely do impact adversely on overall survival. Furthermore, there are many cross-sectional associations between different bone metabolism parameters in CKD (3,4) and outcomes; these include serum phosphate, calcium, PTH, vitamin D and FGF-23 concentrations (4,5). Of note, from the epidemiological point of view there are significant differences between the different analyses in terms of their relationship to patient survival: plasma phosphate has the strongest, graded, relationship between serum concentrations and outcomes, whereas in many studies, there is a ‘U’ shaped relationship for serum PTH concentrations (5–7). The drug cinacalcet, the first clinically available allosteric agonist of the cell-surface calcium-sensing receptor – a ‘calcimimetic’ approved for treatment of SHPT (8) – has a marked ability to suppress both serum calcium and PTH concentrations in CKD (and a rather smaller potential to decrease plasma phosphate concentrations). Much effort over more than two decades has been applied to trying to combat the increased
286
cardiovascular mortality of CKD; these efforts have included altering dialysis ‘dose’, dialysis type/membrane, clearances of uraemic middle molecules, concentrations of haemoglobin, cholesterol, homocysteine, type of oral phosphate binder, and the use of antioxidant therapy (2). Using cinacalet (8,9) can potentially help address the association between elevated PTH, calcium and phosphate concentrations with adverse outcomes, as cinacalcet acts on all three of these simultaneously (at least in short-term administration studies). Cinacalcet use in some countries is limited by national guidelines (e.g.: in UK influenced by the HTA/NICE guidance 10) or by a comprehensive capitation reimbursement system (e.g. Romania, Hungary, Portugal), in marked contrast with much more liberal use of this expensive new therapy in many Southern European countries.
The extremely high morbidity and mortality experienced by subjects with chronic kidney disease (CKD) has often been described and reviewed (1), but this familiarity should not breed indifference to the huge burden of premature cardiovascular disease – something which becomes more obvious, but increasingly challenging to treat, as GFR declines, or proteinuria increases (1,2). The health outcomes for a middle-aged person entering renal replacement therapy are as bad as those seen with a major solidorgan malignancy; while there has been modest progress in improving outcomes over the last two decades, the diagnosis of significant or progressive CKD should and thus still does continue to cast a shadow over patients, carers and healthcare professionals alike.
The EVOLVE study The EVOLVE study was a multicentre, prospective, randomised, placebo-controlled trial in which the use of cinacalcet vs. placebo was assessed in 3883 adults undergoing dialysis (9). All the patients were eligible to receive conventional therapy, including phosphate binders, vitamin D compounds or both. Randomisation was stratified according to country and diabetes status with the use of fixed blocks. The sponsor, investigators and patients were unaware of the treatment assignments (9). After randomisation, patients received either cinacalcet or placebo at a starting dose of 30 mg daily, thereafter the dose was titrated against serum PTH concentration Dialysis, phosphate binders, vitamin D sterols, calcium supplements and other medications were prescribed at the discretion of the treating physicians, who were encouraged to adhere to published clinical-practice guidelines [which changed significantly during the trial itself (11)]. The primary composite end-point was the time to death or the first non-fatal cardiovascular event (myocardial infarction, hospitalisation for unstable angina, heart failure or a peripheral vascular event).
ª 2014 John Wiley & Sons Ltd Int J Clin Pract, March 2014, 68, 3, 286–289. doi: 10.1111/ijcp.12261
Perspective
Secondary end-points included the time to the individual components of the primary composite endpoint, death from cardiovascular causes, stroke, bone fracture and parathyroidectomy (9,12). The proposed sample size was based on the following assumptions: an annual rate of the primary composite end-point of 23.2% in the placebo group, a 20% treatment effect, a 1.5-year enrolment period, a 4-year total study duration, an annual rate of loss to follow-up of 1%, an annual rate of drop out (withdrawal from active treatment before a primary event) of 10% in the cinacalcet group and a rate of drop-in (use of commercially available cinacalcet before a primary event) of 10% in the placebo group. After it became apparent that the overall (blinded) event rate was well below 20.8%, the trial duration was then extended by 16 months to allow for accrual of the requisite number of events. In the 3883 subjects who were randomised from 22 countries, including the USA, Canada, Australia, three Latin American nations, Russia and 15 European nations, the burden of overt cardiovascular disease at baseline was high (e.g. myocardial infarction 12.4%, heart failure 23.3%). The median plasma parathyroid hormone concentration at baseline was 692 pg/mL (10%, 90% range, 363–1694 pg/ml). At baseline, 87.2% of subjects were prescribed phosphate binders and 57.5% were prescribed active vitamin D compounds. Demographic data, comorbid conditions and baseline laboratory data varied significantly across regions (10,12). The daily median cinacalcet dose was 55 mg (10th–90th percentile, 28–130 mg) for cinacalcet and 125 mg (10th–90th percentile, 43–161 mg) for placebo. A total of 80.0% of patients in the placebo group reached the maximum daily dose, as compared with 38.3% of those in the cinacalcet group. Figure 2 from the original publication shows the cumulative incidence of discontinuation of the study drug. Using the original assumption of a 20% treatment effect, but with the observed study duration and observed rates of events, drop out and drop-in rates, which were assumed to be constant, the statistical power was re-estimated to be only 54% (from the previous 90%). The primary composite end-point was reached in 938 of 1948 patients (48.2%) in the cinacalcet group, as compared with 952 of 1935 patients (49.2%) in the placebo group. So, this was a negative outcome study (10). Put another way, in an unadjusted intention-to-treat analysis, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe biochemical secondary hyperparathyroidism who were undergoing dialysis. Yet, the reason for this was not lack ª 2014 John Wiley & Sons Ltd Int J Clin Pract, March 2014, 68, 3, 286–289
of biochemical efficacy of the primary intervention, as the two groups were clearly separated by the marked impact of cinacalcet on serum PTH and calcium concentrations, maintained over a long duration. The effect of cinacalcet was definitely more pronounced among older patients (p = 0.03 for interaction). It seemed to be more evidently effective in those with PTH concentrations < 900 pg/ml (which seems counter-intuitive if the hypothesis being tested is essentially the ‘toxicity’ of elevated calcium and PTH). Hypocalcaemia developed in seven times as many patients in the cinacalcet group as in the placebo group, and nausea and vomiting were twice as common with cinacalcet. Adverse effects led to discontinuation of the study drug in 18.1% of patients in the cinacalcet group and 13.0% of those in the placebo group. Rates of serious adverse events were similar in the two groups.
Analysis and context So, another large and expensive (for CKD) study, lasting around 6 years, was duly undertaken, but this yielded nothing ‘practice changing’ at the end of all of that worthy effort. Why not, we might legitimately ask? There are quite a large number of observations that need to be made about this trial. First, and the only one given in praise, is recognition of the huge effort and determination involved to mount a study in a complex group of patients such as those on dialysis. That is, however, the point where the praise ceases, and from now one, there is criticism and censure. Let us re-examine the trial substrate – subjects on haemodialysis. The median age was around 55, and the median time on dialysis prior to enrolment into the trial was 45 months (10–90% 8.5– 190 months). The median age for starting dialysis in the USA and UK is around 65–70 years, and the first year’s mortality post dialysis commencement is significantly higher than the 3 years that follow (13). So, clearly, a younger cohort with a survival ‘advantage’ was the main subject material of the trial, which itself would render any trial outcomes difficult to extrapolate, as would the issues around side effects, and discontinuations. This might explain the lower than predicted overall event rates, and thus the need to extend the trial duration to await the collection of enough events to permit sufficient statistical power. Moreover, it is very clear that the younger subjects in the trial failed to yield sufficient events compared with the older subjects; indeed, age remains much the most potent factor in determining outcomes on dialysis. The forest plot for the interaction of outcome with age clearly shows that any
287
288
Perspective
‘traction’ on outcomes that could be obtained by the use of cinacalcet was only seen in those aged over 60 years, and, curiously, in those with PTH concentrations < 900 pg/ml. We believe that this element of trial design was a serious misjudgement – allowing subjects aged from 18 to 80 to be enrolled – with a mild biochemical abnormality in many cases – this study would have been possible to conduct much faster, and possibly with a different outcome, had the age range been 50–80 years and the serum PTH concentration inclusion range more relevant. The additional time this study took to complete allowed an ever greater number of people to drop out, and most importantly, to drop-in, to the study – the rate at which patients on placebo ended up taking cinacalcet was (at around 27%) a very major concern and must be seen as a profound disappointment; much more effort should have been undertaken by the trial sponsors to prevent this from happening. Equally, up to 40% of placebo patients did not receive vitamin D therapy, and around 15% of patients did not receive oral phosphate binders (9). The use of calcimimetics without concurrent use of vitamin D therapy is neither typical nor sufficiently explored by other trials to be recommendable for clinical use. Not only was this ‘age/risk homogenisation’ a consequence of the trial design, but the composite endpoint was too broad and unfocussed. This is relevant as the primary entry criterion was a simple elevation of plasma PTH concentration (to within a range of 300–800 pg/ml). Elevation of plasma PTH concentration at this level has negligible effects on outcomes and survival, does not constitute a ‘condition’ (and in particular it does not constitute hyperparathyroidism except in a very narrow, biochemical, sense) and thus is not precise enough biologically to be a major selection criterion for trial inclusion. The relatively normal bone turnover markers, including bone-specific alkaline phosphatase, and the lack of impact of the use of cinacalcet on any bone-related outcome (e.g. fracture), tellingly make this point. In our view, a very significant proportion of the subjects enrolled into this study did not have a condition that could reasonably have warranted the use of the drug being studied! This implies that in the investigators’ minds diseases can be defined purely biochemically, which is regrettable. Another very telling statistic about the ‘mildness’ of any hyperparathyroidism seen in this EVOLVE study is that unlike the registration studies for cinacalcet reported in aggregate in 2005, where the median cinacalcet dose was 93 mg/day (14), in the EVOLVE study the median dose was around 55 mg. Even with this lower dose employed, the prevalence of nausea and vomiting was significant on
active treatment, and it will be interesting to see if any quality of life domains were helpfully influenced; our prediction is that this will prove to be negative too. Not long after the full publication of EVOLVE there was a Cochrane review of the use of cinacalcet in nephrology. Cochrane and Embase databases (through 7 February 2013) were electronically searched to identify randomised trials evaluating effects of calcimimetic therapy on mortality and adverse events in adults with CKD (15). Two independent reviewers identified trials, extracted data, and assessed risk of bias. Eighteen trials comprising 7446 participants compared cinacalcet plus conventional therapy with placebo or no treatment plus conventional therapy in adults with CKD. In moderate- to high-quality evidence in adults with CKD stage 5D (dialysis), cinacalcet had little or no effect on all-cause mortality [relative risk, 0.97 (95% confidence interval, 0.89–1.05)], had imprecise effect on cardiovascular mortality [0.67 (0.16–2.87)], and prevented parathyroidectomy [0.49 (0.40–0.59)] and hypercalcaemia [0.23 (0.05–0.97)], but increased hypocalcaemia [6.98 (5.10–9.53)], nausea [2.02 (1.45–2.81)] and vomiting [1.97 (1.73-2.24)]. On average, treating 1000 people with CKD stage 5D for 1 year had no effect on survival and prevented about three patients from experiencing parathyroidectomy (PTX), whilst 60 experienced hypocalcaemia and 150 experienced nausea. These effects would be challenging indeed for a drug as cheap as aspirin. Cinacalcet is somewhat more costly than that per patient year administation (currently around $250,000,000 per annum cost in the USA).
Conclusions Cinacalcet reduces the need for PTX in patients with CKD stage 5D, although, as there was local flexibility about what constituted suitable grounds for surgical PTX intervention, this statement needs to be carefully qualified. If the decision to proceed to were exclusively related with the degree of serum PTH concentration elevation, without symptoms, this would be a most different set of patients to those undergoing PTX for bone pain, myopathy and fractures. Cinacalcet use in this population seemed to have no impact on CV or total mortality despite sustained impact on the ‘biochemical risk’ for adverse outcomes. Where does this leave ‘CKD-MBD’ as a clinical concept? In our view, the lack of impact on hard outcomes by significant manipulation of serum PTH and calcium concentrations seriously questions the CKD-MBD concept, and even some of the KDIGO ª 2014 John Wiley & Sons Ltd Int J Clin Pract, March 2014, 68, 3, 286–289
Perspective
CKD-MBD biochemical ‘targets’ proposed in 2009 (11). Nephrology research directions now urgently need to be refocussed around key questions, which if answered, might impact patient outcomes substantially and meaningfully. Is it possible to slow the CKD progression and attenuate comorbidities? Can replacement with fixed doses of compounds known to be deficient in CKD, ever lead to improved outcomes? Will it be possible to fund such studies, given that some of the simple, sometimes complementary, therapies offer little financial return for industry – the traditional funder of first, or last, resort for nephrology (16)? Should we not now concentrate on nested care ‘bundles’ of interventions in one well-conducted study, and by so doing, grasp the opportunity to show that we can actually influence patient-level (as opposed to biochemical) outcomes positively? After all, diabetologists have shown us that this style and type of trial in a
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complex population can be undertaken (17). Do we need in addition to embrace complementary and different methodologies and issues that need to be addressed to design studies to address key questions? We think the answer to all of these questions is ‘yes, we do’!
Disclosure None. 1
D. Goldsmith,1 A. Covic2 Nephrology, Guy’s Hospital, King’s Health Partners, London, UK 2 Renal Department, Parhon Hospital, Iasi, Romania
Correspondence to: David Goldsmith, Nephrology, Guy’s Hospital, King’s Health Partners, London, UK Tel.: 02071887188 Fax: 02071885646 Email: [email protected]
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Paper received July 2013, accepted July 2013
