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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 | 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://cjasn.asnjournals.org/content/2/5/898.full.pdf+html</ref><ref name=":0">http://www.nature.com/ki/journal/v82/n1/full/ki201269a.html</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</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 | 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 | The primary endpoint of either time to death or first cardiovascular event showed no significant difference between groups. However, a prespecified analysis of study results accounting for high dropout rates (lag-censoring analysis) revealed a 15% relative hazard reduction in the composite primary endpoint and a 7% relative hazard reduction in mortality. Another analysis adjusting for differences in baseline characteristics similarly found an 11% relative hazard reduction in the composite primary endpoint and an 11% relative hazard reduction in mortality. Controversy exists on how these adjusted analyses should be interpreted. 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" />. | |||
Secondary outcomes demonstrated a reduced need for parathyroidectomy in patients treated with cinacalcet. Despite the reduction in PTH levels, the risk of fracture remained similar in both groups. | Secondary outcomes demonstrated a reduced need for parathyroidectomy in patients treated with cinacalcet. Despite the reduction in PTH levels, the risk of fracture remained similar in both groups. | ||
==Guidelines== | ==Guidelines== | ||
=== KDIGO CKD-BMD | === KDIGO CKD-BMD 2009<ref>http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO%20CKD-MBD%20GL%20KI%20Suppl%20113.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>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</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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==Interventions==<!-- remove when cleared by an editor --> | ==Interventions==<!-- remove when cleared by an editor --> | ||
* Randomization by blocks according to country and diabetes status | * Randomization by blocks according to country and diabetes status | ||
* Cinacalcet group: | * All groups received conventional therapy: | ||
** Dialysis, phosphate binders, vitamin D sterols, calcium supplements, other medications | |||
** Prescribed at the discretion to the treating physicians encouraged to follow clinical practice guidelines | |||
* Cinacalcet group received: | |||
** Starting dose of 30mg daily | ** Starting dose of 30mg daily | ||
** Eligible for dose escalation once every 4 weeks during a 20 week escalation phase, or every 8 weeks during followup | ** Eligible for dose escalation once every 4 weeks during a 20 week escalation phase, or every 8 weeks during followup | ||
** Escalation based on PTH and serum Ca | ** Escalation based on PTH and serum Ca | ||
* Placebo group: | * Placebo group received: | ||
** Same doses and dosing protocol as treatment group | ** Same doses and dosing protocol as treatment group | ||
* | ** | ||
* | |||
==Outcomes== | ==Outcomes== | ||
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* 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>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/</ref> | ||
* Combination of atherosclerotic and non-atherosclerotic endpoints | * Combination of atherosclerotic and non-atherosclerotic endpoints | ||
** Cinacalcet hypothesized to primarily effect non-atherosclerotic endpoints (slowing arterial calcification, reducing myocardial calcium accumulation)<ref>http://cjasn.asnjournals.org/content/2/1/89.full</ref> | ** Cinacalcet hypothesized to primarily effect non-atherosclerotic endpoints (slowing arterial calcification, reducing myocardial calcium accumulation)<ref>http://cjasn.asnjournals.org/content/2/1/89.full</ref> | ||