Guideline:
Cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy
Bibliographic Source(s)
- National Institute for Health and Clinical Excellence (NICE). Cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Jan. 28 p. (Technology appraisal guidance; no. 117).
Guideline Status
This is the current release of the guideline.
Guideline Category
Assessment of Therapeutic Effectiveness
Treatment
Intended Users
Advanced Practice Nurses
Nurses
Physician Assistants
Physicians
Guideline Objective(s)
To establish the effectiveness and cost-effectiveness of cinacalcet for the treatment of secondary hyperparathyroidism for people on dialysis due to end-stage renal disease
Target Population
Patients with secondary hyperparathyroidism in end-stage renal disease and on maintenance dialysis therapy
Interventions and Practices Considered
- Cinacalcet
- Regular monitoring of the response to treatment
Major Outcomes Considered
- Clinical effectiveness
- Mortality
- Incidence of cardiovascular events
- Incidence of fractures
- Health-related quality of life
- Symptoms related to hyperparathyroidism
- Plasma parathyroid hormone calcium phosphate and calcium x phosphate product levels
- Parathyroidectomy
- Hospitalization
- Adverse effects
- Cost-effectiveness
Methods Used to Collect/Select Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Searches of Unpublished Data
Description of Methods used to Collect/Select the Evidence
Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an assessment report. The assessment report for this technology appraisal was prepared by the Peninsula Technology Assessment Group Peninsula Medical School (see the "Availability of Companion Documents" field.)
Clinical Effectiveness
Inclusion and Exclusion Criteria
Inclusion
Intervention:
Cinacalcet hydrochloride (HCI) in licensed doses
Comparators:
Placebo or "Standard care" which may include:
- Phosphate binders
- Vitamin D
- Parathyroidectomy
Population:
People with hyperparathyroidism secondary to end-stage renal disease (ESRD) on peritoneal or haemodialysis
Study Design:
Randomised controlled trials (RCTs) with at least 12 weeks follow up
Outcomes:
- Mortality
- Incidence of cardiovascular events
- Incidence of fractures
- Health related quality of life
- Symptoms related to hyperparathyroidism
- Serum PTH calcium phosphate and calcium x phosphate product levels
- Parathyroidectomy
- Hospitalisation
- Adverse effects
Exclusion Criteria
Population:
- People with renal disease not on dialysis
- Primary hyperparathyroidism
Study Design:
- RCTs with less than 12 weeks follow up
- Study designs other than RCTs
Search Strategy
Electronic databases were searched for published systematic reviews RCTs economic evaluations and ongoing research in March 2005 and updated in February 2006. Appendix 8.4 of the Assessment Report (see "Availability of Companion Documents" field) shows the databases searched and the strategy in full. Bibliographies of articles were also searched for further relevant studies and the U.S. Food and Drug Administration (FDA) website was searched for relevant material.
Identification of Studies
Relevant studies were identified in two stages. Abstracts returned by the search strategy were examined independently by two researchers and screened for inclusion or exclusion. Disagreements were resolved by discussion. Full texts of the identified studies were obtained. Two researchers examined these independently for inclusion or exclusion and disagreements were resolved by discussion. The process is illustrated in Appendix 8.5 of the Assessment Report (see "Availability of Companion Documents" field).
Cost-Effectiveness
Search Strategy
Electronic databases were searched using the strategy shown in Appendix 3 of the Assessment Report (see "Availability of Companion Documents" field).
Inclusion and Exclusion Criteria
Studies were included if they were cost-utility analyses of cinacalcet compared with standard treatment for people with end-stage renal disease on dialysis with secondary hyperparathyroidism.
Number of Source Documents
Clinical Effectiveness
The systematic review identified seven published reports of randomized controlled trials (RCTs) of cinacalcet versus placebo in people with hyperparathyroidism secondary to end-stage renal disease who were receiving dialysis. Most of these publications reported on one or more of four RCTs sponsored by the manufacturer of cinacalcet although three smaller RCTs were also identified. In addition the manufacturer submitted information on an unpublished study relating to an RCT designed to evaluate optimal levels of concomitant vitamin D and phosphate binders in patients receiving standard care with or without cinacalcet.
Cost-Effectiveness
- No cost-utility studies in the relevant populations were identified.
- One cost-utility study was submitted to the National Institute for Health and Clinical Excellence (NICE) appraisal process by the manufacturer.
Methods Used to Assess the Quality and Strength of the Evidence
Expert Consensus
Rating Scheme for the Strength of the Evidence
Not applicable
Methods Used to Analyze the Evidence
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence
Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an assessment report. The assessment report for this technology appraisal was prepared by the Peninsula Technology Assessment Group Peninsula Medical School (see the "Availability of Companion Documents" field.)
Data Extraction Strategy
Data were independently extracted by two researchers. Disagreements were resolved by discussion. Actual numbers were extracted where possible. In some cases data had to be extracted from graphs and may be subject to inaccuracies. Such data is identified in the data extraction sheets. Data extraction forms for each included study are shown in Appendix 7 of the Assessment Report (see the "Availability of Companion Documents" field).
Quality Assessment Strategy
Assessments of randomised controlled trial (RCT) quality were performed using the indicators shown below. Results were tabulated and these aspects described.
Internal Validity
Sample Size
Power calculation at design
Selection Bias
- Explicit eligibility criteria
- Proper randomisation and allocation concealment
- Similarity of groups at baseline
Performance Bias
Similarity of treatment other than the intervention across groups
Attrition Bias and Intention to Treat Analysis
- All patients are accounted for
- Number of withdrawals specified and reasons described
- Analysis undertaken on an intention to treat (ITT) basis
Detection Bias
- Blinding
- Objective outcome measures
- Appropriate data analysis
Any potential conflict of interest was noted (for example financial support provided to studies and/or authors by manufacturers of the interventions).
External Validity
External validity was judged according to the ability of a reader to consider the applicability of findings to a patient group in practice. Study findings can only be effectively generalisable if they (a) describe a cohort that is representative of the affected population at large or (b) present sufficient detail in their outcome data to allow the reader to extrapolate findings to a patient group with different characteristics.
Generalisability of included studies was assessed by examining the age sex and race profile of the included patients as well as their baseline mineral and parathyroid hormone (PTH) serum levels. Studies that were representative of the United Kingdom (UK) population with regard to these factors were judged to have high external validity.
Methods of Analysis
Details of the methodology and results of included trials are tabulated and described in the text of the Assessment Report (see the "Availability of Companion Documents" field). Results from RCTs are presented in the same tables; where study design renders cells inapplicable they have been greyed out. Dashes in the tables indicate the information was not reported. Where calculated by the authors chi-square statistics were derived using the CHIDIST function of Microsoft Excel.
The assessment group did not combine the results using meta-analysis because the major trials have already been reported in combination using patient level data.
Most of the papers report outcome measure in metric units. The assessment group has adjusted these in order to present them in standard units using the conversion factors shown in Table 13 of the Assessment Report (see the "Availability of Companion Documents" field.
Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations
Considerations
Technology appraisal recommendations are based on a review of clinical and economic evidence.
Technology Appraisal Process
The National Institute for Health and Clinical Excellence (NICE) invites 'consultee' and 'commentator' organisations to take part in the appraisal process. Consultee organisations include national groups representing patients and carers the bodies representing health professionals and the manufacturers of the technology under review. Consultees are invited to submit evidence during the appraisal and to comment on the appraisal documents.
Commentator organisations include manufacturers of the products with which the technology is being compared the National Health Service (NHS) Quality Improvement Scotland and research groups working in the area. They can comment on the evidence and other documents but are not asked to submit evidence themselves.
NICE then commissions an independent academic centre to review published evidence on the technology and prepare an 'assessment report'. Consultees and commentators are invited to comment on the report. The assessment report and the comments on it are then drawn together in a document called the evaluation report.
An independent Appraisal Committee then considers the evaluation report. It holds a meeting where it hears direct spoken evidence from nominated clinical experts patients and carers. The Committee uses all the evidence to make its first recommendations in a document called the 'appraisal consultation document' (ACD). NICE sends all the consultees and commentators a copy of this document and posts it on the NICE website. Further comments are invited from everyone taking part.
When the Committee meets again it considers any comments submitted on the ACD; then it prepares its final recommendations in a document called the 'final appraisal determination' (FAD). This is submitted to NICE for approval.
Consultees have a chance to appeal against the final recommendations in the FAD. If there are no appeals the final recommendations become the basis of the guidance that NICE issues.
Who is on the Appraisal Committee?
NICE technology appraisal recommendations are prepared by an independent committee. This includes health professionals working in the NHS and people who are familiar with the issues affecting patients and carers. Although the Appraisal Committee seeks the views of organisations representing health professionals patients carers manufacturers and government its advice is independent of any vested interests.
Rating Scheme for the Strength of the Recommendations
Not applicable
Cost Analysis
The systematic review carried out by the Assessment Group did not identify any published cost-effectiveness studies relevant to the scope of this appraisal. An economic model and separate cost–consequence analysis were submitted by the manufacturer of cinacalcet and the Assessment Group developed its own economic model. Both models were cost–utility analyses comparing cinacalcet in addition to standard care (using vitamin D and phosphate binders) with standard care only in patients with secondary hyperparathyroidism (parathyroid hormone [PTH] >31.6 pmol/litre) who were receiving dialysis. Both analyses adopted the perspective of the National Health Service (NHS) and generally similar cost and resource-use assumptions were used. There were however differences between the models in the assumptions driving effectiveness.
The model submitted by the manufacturer incorporated health states reflecting patients' status in relation to adverse events associated with secondary hyperparathyroidism. Clinical events included in the analysis were cardiovascular hospitalisations fractures (major and minor) parathyroidectomies and death. The effect of cinacalcet on the relative risks for these outcomes was based on the pooled results of four clinical trials. The manufacturer's model resulted in an incremental cost-effectiveness ratio (ICER) of 35600 pounds sterling per quality-adjusted life year (QALY) gained. Subgroup analyses in patients with moderate (PTH 31.6 to 84.2 pmol/litre) and severe (PTH > 84.2 pmol/litre) secondary hyperparathyroidism resulted in ICERs of 30400 pounds sterling and 48300 pounds sterling per QALY gained respectively. Various one-way sensitivity analyses were conducted. The results of these indicated that the ICER was most sensitive to variations in the dose of cinacalcet.
The Assessment Group's approach differed from that of the manufacturer in that they modelled the effect of treatment on PTH levels and then related this intermediate endpoint to clinical events. In the base-case analysis patients in both arms were stratified by PTH levels. These were defined as 'controlled' (PTH 32 pmol/litre or less) 'uncontrolled' (PTH 33 to 84 pmol/litre) or 'very uncontrolled' (PTH 85 pmol/litre or more). Patients in the 'very uncontrolled' group were stratified further according to whether or not they had undergone parathyroidectomy (with or without adverse surgical events). Clinical events included cardiovascular events fractures and death and the probabilities of these occurring at different PTH levels were derived from a variety of different sources mostly large cohort studies. These estimates of probability rely on a number of assumptions and are subject to uncertainty. The reduction in utility associated with an adverse event was greater in the 3 months after the event than in subsequent cycles of the model. Utility increased for subsequent cycles but to a level that was lower than the utility before the event. The costs associated with cinacalcet the treatment of adverse events parathyroidectomy monitoring of patients and concomitant medications were included in the model. It was assumed that a proportion of patients with 'very uncontrolled' PTH levels and no patients with 'controlled' or 'uncontrolled' PTH levels would be taking non-calcium-based phosphate binders. A wide range of sensitivity analyses were conducted. The costs of dialysis were excluded from the base-case analysis but included in a sensitivity analysis.
See section 4.2 in the original guideline document for a detailed discussion of cost effectiveness models from the manufacturer and the Assessment Group.
Method of Guideline Validation
External Peer Review
Description of Method of Guideline Validation
Consultee organizations from the following groups were invited to comment on the draft scope Assessment Report and the Appraisal Consultation Document (ACD) and were provided with the opportunity to appeal against the Final Appraisal Determination.
- Manufacturer/sponsors
- Professional/specialist and patient/carer groups
- Commentator organisations (without the right of appeal)
In addition individuals selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups were also invited to comment on the ACD.
Major Recommendations
- Cinacalcet is not recommended for the routine treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy.
- Cinacalcet is recommended for the treatment of refractory secondary hyperparathyroidism in patients with end-stage renal disease (including those with calciphylaxis) only in those:
- Who have "very uncontrolled" plasma levels of intact parathyroid hormone (defined as greater than 85 pmol/litre [800 pg/mL]) that are refractory to standard therapy and a normal or high adjusted serum calcium level and
- In whom surgical parathyroidectomy is contraindicated in that the risks of surgery are considered to outweigh the benefits
- Response to treatment should be monitored regularly and treatment should be continued only if a reduction in the plasma levels of intact parathyroid hormone of 30% or more is seen within 4 months of treatment including dose escalation as appropriate.
Clinical Algorithm(s)
None provided
Type of Evidence supporting the Recommendations
The type of evidence supporting the recommendations is not specifically stated.
Potential Benefits
Appropriate use of cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy
Potential Harms
The most commonly reported adverse effects in clinical trials were nausea and vomiting. These were mild to moderate in nature and transient in most cases.
For full details of side effects and contraindications see the Summary of Product Characteristics (SPC) available at http://emc.medicines.org.uk/.
Contraindications
Because cinacalcet lowers calcium levels it is contraindicated if serum calcium is below the lower limit of the normal range.
For full details of contraindications see the Summary of Product Characteristics (SPC) available at http://emc.medicines.org.uk/.
Qualifying Statements
This guidance represents the view of the Institute which was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. The guidance does not however override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient in consultation with the patient and/or guardian or carer.
Description of Implementation Strategy
Implementation
- The Healthcare Commission assesses the performance of National Health Services (NHS) organizations in meeting core and developmental standards set by the Department of Health in "Standards for better health" issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by National Institute for Health and Clinical Excellence (NICE) technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals.
- "Healthcare standards for Wales" was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 which requires Local Health Boards and NHS Trusts to make funding available to enable the implementation of NICE technology appraisal guidance normally within 3 months.
- NICE has developed tools to help organisations implement this guidance (listed below). These are available on NICE website (www.nice.org.uk/TA114) (see also the "Availability of Companion Documents" field).
- Local costing template incorporating a costing report to estimate the savings and costs associated with implementation.
- Audit criteria to monitor local practice
Implementation Tools
Audit Criteria/Indicators
Patient Resources
Quick Reference Guides/Physician Guides
Resources
For information about availability see the "Availability of Companion Documents" and "Patient Resources" fields below.
IOM Care Need
Getting Better
Living with Illness
IOM Domain
Effectiveness
Patient-centeredness
Bibliographic Source(s)
- National Institute for Health and Clinical Excellence (NICE). Cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Jan. 28 p. (Technology appraisal guidance; no. 117).
Adaptation
Not applicable: The guideline was not adapted from another source.
Source(s) of Funding
National Institute for Health and Clinical Excellence (NICE)
Guideline Committee
Appraisal Committee
Composition of Group that Authored the Guideline
Committee Members: Dr Jane Adam Radiologist St George's Hospital London; Professor A E Ades MRC Senior Scientist MRC Health Services Research Collaboration Department of Social Medicine University of Bristol; Dr Amanda Adler Consultant Physician Addenbrooke's Hospital Cambridge; Dr Tom Aslan General Practitioner Stockwell London; Professor David Barnett (Chair) Professor of Clinical Pharmacology University of Leicester; Mrs Elizabeth Brain Lay member; Dr Karl Claxton Health Economist University of York; Dr Richard Cookson Senior Lecturer in Health Economics School of Medicine Health Policy and Practice University of East Anglia; Mrs Fiona Duncan Clinical Nurse Specialist Anaesthetic Department Blackpool Victoria Hospital; Professor Christopher Eccleston Director Pain Management Unit University of Bath; Dr Paul Ewings Statistician Taunton and Somerset NHS Trust Taunton; Professor John Geddes Professor of Epidemiological Psychiatry University of Oxford; Mr John Goulston Director of Finance Barts and the London NHS Trust; Mr Adrian Griffin Health Outcomes Manager Johnson & Johnson Medical; Ms Linda Hands Consultant Surgeon John Radcliffe Hospital Oxford; Dr Elizabeth Haxby Lead Clinician in Clinical Risk Management Royal Brompton Hospital London; Dr Rowan Hillson Consultant Physician Diabeticare The Hillingdon Hospital Uxbridge; Dr Catherine Jackson Clinical Senior Lecturer in Primary Care Medicine University of Dundee; Professor Richard Lilford Professor of Clinical Epidemiology Department of Public Health and Epidemiology University of Birmingham; Dr Simon Mitchell Consultant Neonatal Paediatrician St Mary's Hospital Manchester; Ms Judith Paget Chief Executive Caerphilly Local Health Board Wales; Dr Katherine Payne Health Economist The North West Genetics Knowledge Park University of Manchester; Dr Ann Richardson Independent Research Consultant; Dr Stephen Saltissi Consultant Cardiologist Royal Liverpool University Hospital; Mr Mike Spencer General Manager Clinical Support Services Cardiff and Vale NHS Trust; Professor Andrew Stevens (Vice Chair) Professor of Public Health University of Birmingham; Dr Cathryn Thomas General Practitioner Sutton Coldfield West Midlands; Associate Professor Department of Primary Care and General Practice University of Birmingham; Simon Thomas Consultant Physician General Medicine and Clinical Pharmacology Newcastle Hospitals NHS Trust; Dr Norman Vetter Reader Department of Epidemiology Statistics and Public Health College of Medicine University of Wales Cardiff; Professor Mary Watkins Professor of Nursing University of Plymouth; Dr Paul Watson Medical Director Essex Strategic Health Authority
Financial Disclosures/Conflicts of Interest
Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest the member is excluded from participating further in that appraisal.
Guideline Status
This is the current release of the guideline.
Guideline Availability
Electronic copies: Available in Portable Document Format (PDF) format from the National Institute for Health and Clinical Excellence (NICE) Web site.
Availability of Companion Documents
The following are available:
- Cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy. Quick reference guide. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Jan. 2 p. (Technology appraisal 117). Available in Portable Document Format (PDF) from the National Institute for Health and Clinical Excellence (NICE) Web site.
- Costing statement: Hyperparathyroidism - cinacalcet HCI. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Jan. 2 p. (Technology appraisal 117). Available from the National Institute for Health and Clinical Excellence (NICE) Web site.
- Cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy. Audit criteria. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Jan. 11 p. (Technology appraisal 117). Available from the National Institute for Health and Clinical Excellence (NICE) Web site.
- The effectiveness and cost-effectiveness of cinacalcet for secondary hyperparathyroidism in end stage renal disease patients on dialysis: a systematic review and economic evaluation. Assessment report. Peninsula Technology Assessment Group (PenTAG) University of Southampton. 2006 Mar 16. Electronic copies: Available from the NICE Web site.
Print copies: Available from the National Health Service (NHS) Response Line 0870 1555 455. ref: N1184. 11 Strand London WC2N 5HR.
Patient Resources
The following is available:
- Cinacalcet for treating secondary hyperparathyroidism in people with kidney disease who are on dialysis. Understanding NICE guidance - Information for people who use NHS services. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Jan. 5 p. (Technology appraisal 117).
Electronic copies: Available in Portable Document Format (PDF) from the National Institute for Health and Clinical Excellence (NICE) Web site.
Print copies: Available from the NHS Response Line 0870 1555 455. ref: N1185. 11 Strand London WC2N 5HR.
Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.
NGC STATUS
This NGC summary was completed by ECRI Institute on June 26 2007.
The National Institute for Health and Clinical Excellence (NICE) has granted the National Guideline Clearinghouse (NGC) permission to include summaries of their Technology Appraisal guidance with the intention of disseminating and facilitating the implementation of that guidance. NICE has not verified this content to confirm that it accurately reflects the original NICE guidance and therefore no guarantees are given by NICE in this regard. All NICE technology appraisal guidance is prepared in relation to the National Health Service in England and Wales. NICE has not been involved in the development or adaptation of NICE guidance for use in any other country. The full versions of all NICE guidance can be found at www.nice.org.uk.
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Tools
No Quick Reference tools have been developed.