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==Major Points==<!-- remove when cleared by an editor --> | ==Major Points==<!-- remove when cleared by an editor --> | ||
Secondary hyperparathyroidism in chronic kidney disease patients is a non-traditional risk factor for cardiovascular disease. High serum parathryoid hormone levels (PTH) promotes vascular and cardiac valvular calcification, and is associated with increased arterial stiffness and left ventricular hypertrophy<ref> | Secondary hyperparathyroidism in chronic kidney disease patients is a non-traditional risk factor for cardiovascular disease. High serum parathryoid hormone levels (PTH) promotes vascular and cardiac valvular calcification, and is associated with increased arterial stiffness and left ventricular hypertrophy<ref>[[Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE): Rationale and Design Overviewhttp://cjasn.asnjournals.org/content/2/5/898.full.pdf+html|Chertow GM, et al. "Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE): Rationale and Design Overview." ''CJASN. ''2007;2:898-905.]]</ref><ref name=":0">[http://www.nature.com/ki/journal/v82/n1/full/ki201269a.html Torres PA, Broe MD. "Calcium-sensing receptor, calcimimetics, and cardiovascular calcifications in chronic kidney disease." ''Kidney International. ''2012;82:19-25.]</ref>. Cinacalcet is a calcimimetic agent that primarily acts as an allosteric modulator of the calcium sensing receptor (CaSR). Modulation of parathyroid CaSR receptors reduces serum PTH, calcium, and phosphorus levels<ref>[http://onlinelibrary.wiley.com/doi/10.1592/phco.25.5.709.63595/pdf Byrnes CA, Shepler BM. "Cinacalcet: A New Treatment for Secondary Hyperparathyroidism in Patients Receiving Hemodialysis." ''Pharmacotherapy.'' 2005;25(5):709–716.]</ref>, while modulation of vascular CaSR receptors reduces transcription factor level changes which promote vascular calcification.<ref name=":0" /> | ||
Published in 2012, the '''EV'''aluation '''O'''f Cinacalcet HCl Therapy to '''L'''ower Cardio'''v'''ascular '''E'''vents (EVOLVE) trial was conducted to determine if administration of cinacalcet in dialysis patients reduced cardiovascular death and mortality. This multi-centre, multi-national, blinded randomized control trial enrolled 3883 patients randomized to either cinacalcet or placebo. Drug doses were elevated throughout the trial to meet PTH and calcium targets. Both groups received baseline therapy of phosphate binders, vitamin D, calcium supplements, and dialysis at the discretion of the treating provider. | Published in 2012, the '''EV'''aluation '''O'''f Cinacalcet HCl Therapy to '''L'''ower Cardio'''v'''ascular '''E'''vents (EVOLVE) trial was conducted to determine if administration of cinacalcet in dialysis patients reduced cardiovascular death and mortality. This multi-centre, multi-national, blinded randomized control trial enrolled 3883 patients randomized to either cinacalcet or placebo. Drug doses were elevated throughout the trial to meet PTH and calcium targets. Both groups received baseline therapy of phosphate binders, vitamin D, calcium supplements, and dialysis at the discretion of the treating provider. | ||
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==Guidelines== | ==Guidelines== | ||
=== KDIGO CKD-BMD 2009<ref>http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO%20CKD-MBD%20GL%20KI%20Suppl%20113.pdf</ref> === | === KDIGO CKD-BMD 2009<ref>[http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO%20CKD-MBD%20GL%20KI%20Suppl%20113.pdf 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 International.'' 2009; 76 (Suppl 113): S1–S130.]</ref> === | ||
''These guidelines reflect the outcomes of the EVOLVE trial. The working group of the 2013 KDIGO Controversies Conference did not make changes to the 2009 recommendations.''<ref name=":1">http://www.kdigo.org/ControConf/CKD-MBD%202013/KDIGO%202013%20CKD-MBD%20Controversies%20Conf%20Report%20AOP.pdf</ref> | ''These guidelines reflect the outcomes of the EVOLVE trial. The working group of the 2013 KDIGO Controversies Conference did not make changes to the 2009 recommendations.''<ref name=":1">[http://www.kdigo.org/ControConf/CKD-MBD%202013/KDIGO%202013%20CKD-MBD%20Controversies%20Conf%20Report%20AOP.pdf Ketteler M, et al. "Revisiting KDIGO clinical practice guideline on chronic kidney disease—mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference." ''Kidney International. ''2014.] </ref> | ||
In patients with CKD stage 5D and elevated or rising PTH, we suggest calcitriol, or vitamin D analogs, or calcimimetics, or a combination of calcimimetics and clacitriol or vitamin D analogs be used to lower PTH (2B). | In patients with CKD stage 5D and elevated or rising PTH, we suggest calcitriol, or vitamin D analogs, or calcimimetics, or a combination of calcimimetics and clacitriol or vitamin D analogs be used to lower PTH (2B). | ||
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===Primary Outcome===<!-- remove when cleared by an editor --> | ===Primary Outcome===<!-- remove when cleared by an editor --> | ||
; Time to Death or First Nonfatal Cardiovascular Event | ; Time to Death or First Nonfatal Cardiovascular Event | ||
''Cardiovascular event defined as: MI, unstable angina hospitalization, heart failure, | ''Cardiovascular event defined as: MI, unstable angina hospitalization, heart failure, peripheral vascular event'' | ||
: 48.2% vs. 49.2% (Relative HR=0.93 [CI 0.85-1.02]; p=0.11) | : 48.2% vs. 49.2% (Relative HR=0.93 [CI 0.85-1.02]; p=0.11) | ||
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==Criticisms==<!-- remove when cleared by an editor --> | ==Criticisms==<!-- remove when cleared by an editor --> | ||
* Age-adjusted HR results in statistically significant results for primary outcome, but was not defined as the primary endpoint | * Age-adjusted HR results in statistically significant results for primary outcome, but was not defined as the primary endpoint | ||
** Patients one year older in | ** Patients one year older in cinacalcet group; older age known to increase mortality in dialysis patients | ||
* Censored | * Censored analysis results in statistically significant results for primary outcome, but was not defined as the primary endpoint | ||
* High drug discontinuation rates (66.7% vs. 70.5%) | * High drug discontinuation rates (66.7% vs. 70.5%) | ||
* High drop-in rates in the placebo group (use of commercial cinacalcet) | * High drop-in rates in the placebo group (use of commercial cinacalcet) | ||
* Under the initial assumption of a 20% treatment effect, the study power dropped to 54%<ref name=":2">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983668/</ref> | * Under the initial assumption of a 20% treatment effect, the study power dropped to 54%<ref name=":2">[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983668/pdf/nihms568937.pdf Moe SM, Thadhani R. "What have we learned about CKD-MBD From the EVOLVE and PRIMO trials?" ''Curr Opin Nephrol Hypertens''. 2013; 22(6): 651–655.]</ref> | ||
* Combination of atherosclerotic and non-atherosclerotic endpoints | * Combination of atherosclerotic and non-atherosclerotic cardiovascular endpoints | ||
** Cinacalcet hypothesized to primarily effect non-atherosclerotic endpoints (slowing arterial calcification, reducing myocardial calcium accumulation)<ref>http:// | ** Cinacalcet hypothesized to primarily effect non-atherosclerotic endpoints (slowing arterial calcification, reducing myocardial calcium accumulation)<ref>[http://jaha.ahajournals.org/content/3/6/e001363.full Wheeler DC, et al. "Effects of Cinacalcet on Atherosclerotic and Nonatherosclerotic Cardiovascular Events in Patients Receiving Hemodialysis: The EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial". ''J Am Heart Assoc. ''2014;3:e001363.]</ref> | ||
==Funding==<!-- remove when cleared by an editor --> | ==Funding==<!-- remove when cleared by an editor --> | ||