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| expansion=Effect of Cinacalcet on Cardiovascular Disease in Patients Undergoing Dialysis
| expansion=Effect of Cinacalcet on Cardiovascular Disease in Patients Undergoing Dialysis
| published=2012-12-27
| published=2012-12-27
| author=The EVOLVE Trial Investigators
| author=Chertow GM, et al
| journal=The New England Journal of Medicine
| journal=The New England Journal of Medicine
| year=2012
| year=2012
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| status=Reviewable
| status=Reviewable
| subspecialty=Nephrology
| subspecialty=Nephrology
| disease=Cardiovascular Disease
| disease=Chronic Kidney Disease
| otherDisease1=Chronic Kidney Disease
| otherDisease1=Cardiovascular Disease
| otherDisease2=End Stage Renal Disease
| intervention1=Medicine:Cinacalet
| intervention1=Medicine:Cinacalet
| intervention2=Medicine:Placebo
| intervention2=Medicine:Placebo
| briefDesignDescription=Cinacalcet vs. Placebo in Prevention of Cardiovascular Disease in Dialysis Patients
| briefDesignDescription=Cinacalcet in ESRD
| briefResultsDescription=No difference in clinical outcomes.
| briefResultsDescription=Cinecalcet does not reduce CV events in ESRD
| trainingLevel=Resident
| trainingLevel=Resident
}}
}}


==Clinical Question==<!-- remove when cleared by an editor -->
==Clinical Question==<!-- remove when cleared by an editor -->
Among patients on hemodialysis, does cinacalcet reduce death and cardiovascular events?  
Among ESRD patients undergoing hemodialysis, does cinacalcet reduce death and cardiovascular events?  


==Bottom Line==<!-- remove when cleared by an editor -->
==Bottom Line==<!-- remove when cleared by an editor -->
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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" />.
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 Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (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<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 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" />.
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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 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> ===
=== KDIGO CKD-BMD 2009<ref name="kdigo"/>[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 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>
''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, calcitriol, vitamin D analogs, calcimimetics, or a combination of calcimimetics and clacitriol or vitamin D analogs should be used to lower PTH (2B).


We suggest that, in patients with hypocalcemia, calcimimetics be reduced or stopped depending on severity, concomitant medications, and clinical signs and symptoms (2D).
In patients with hypocalcemia, calcimimetics should be reduced or stopped depending on severity, concomitant medications, and clinical signs and symptoms (2D).


We suggest that, if the intact PTH levels fall below two times the upper limit of normal for the assay, calcitriol, vitamin D analogs, and/or calcimimetics be reduced or stopped (2C).
If the intact PTH levels fall below two times the upper limit of normal for the assay, calcitriol, vitamin D analogs, and/or calcimimetics should be reduced or stopped (2C).


==Design==<!-- remove when cleared by an editor -->
==Design==
* Multicenter, multinational randomized control trial
* Multicenter, multinational randomized control trial
* N=3883
* N=3,883 patients with ESRD
** Cinacalcet and Conventional Therapy (n=1948)
** Cinacalcet and Conventional Therapy (n=1,948)
** Placebo and Conventional Therapy (n=1935)
** Placebo and Conventional Therapy (n=1,935)
*  Follow-up: 5.25 years
*  Follow-up: 5.25 years
* Analysis: Intention-to-treat
* Analysis: Intention-to-treat
* Primary outcome:
* Primary outcome: Death or CV event
**  Time to death or first nonfatal cardiovascular event (MI,  unstable  angina admission, heart failure,  peripheral vascular event)
*  Secondary outcomes:
**  Individual components of primary composite end point
** Death from cardiovascular causes
** Stroke
** Bone fracture
** Parathyroidectomy


==Population==
==Population==
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==Further Reading==
==Further Reading==
<references/>
<references>
<ref name="kdigo">[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>
</references>
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