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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>[http://www.ncbi.nlm.nih.gov/pubmed/17702710 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.ncbi.nlm.nih.gov/pubmed/22437409 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://www.ncbi.nlm.nih.gov/pubmed/15899733 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. | ||
The primary endpoint of either time to death or first cardiovascular event showed a non-significant difference of 7% between groups. However, a prespecified analysis of study results accounting for high dropout rates (lag-censoring analysis) revealed a 12% relative hazard reduction in the composite primary endpoint and a 14% relative hazard reduction in mortality. Another analysis adjusting for differences in baseline characteristics similarly found an 15% relative hazard reduction in the composite primary endpoint and an 17% relative hazard reduction in mortality. Controversy exists on how these adjusted analyses should be interpreted, and some consider the outcomes of this trial to be inconclusive. The KDIGO recommendations on the use of cinacalcet did not change following the publication of this trial<ref name=":1" />. | The primary endpoint of either time to death or first cardiovascular event showed a non-significant difference of 7% between groups. However, a prespecified analysis of study results accounting for high dropout rates (lag-censoring analysis) revealed a 12% relative hazard reduction in the composite primary endpoint and a 14% relative hazard reduction in mortality. Another analysis adjusting for differences in baseline characteristics similarly found an 15% relative hazard reduction in the composite primary endpoint and an 17% relative hazard reduction in mortality. Controversy exists on how these adjusted analyses should be interpreted, and some consider the outcomes of this trial to be inconclusive<ref>[http://www.ncbi.nlm.nih.gov/pubmed/24402624 Locatelli F, et al. "What can we learn from a statistically inconclusive trial? Consensus conference on the EVOLVE study results." ''G Ital Nefrol.'' 2013;30(5).]</ref>. The KDIGO recommendations on the use of cinacalcet did not change following the publication of this trial<ref name=":1" />. | ||
The study was significantly underpowered secondary to high dropout rates secondary to side effects in both groups, as well as high cross-over rates in the placebo group to commercial cinacalcet<ref name=":2" />. | The study was significantly underpowered secondary to high dropout rates secondary to side effects in both groups, as well as high cross-over rates in the placebo group to commercial cinacalcet<ref name=":2" />. | ||
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* 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> | * 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 cardiovascular 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://www.ncbi.nlm.nih.gov/pubmed/25404192 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 --> | ||