EVOLVE: Difference between revisions

| intervention1=Medicine:Cinacalet

| briefResultsDescription=Cinecalcet does not reduce CV events in ESRD

==Clinical Question==<!-- remove when cleared by an editor -->

Among ESRD patients undergoing hemodialysis, does cinacalcet reduce death and cardiovascular events?  

==Bottom Line==<!-- remove when cleared by an editor -->

Cinacalcet does not reduce death and cardiovascular events among patients on hemodialysis.

==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>[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" />.

 

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" />.

 

'''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>, adapted)

''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, calcitriol, vitamin D analogs, calcimimetics, or a combination of calcimimetics and clacitriol or vitamin D analogs should be used to lower PTH (2B).

 

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

 

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).

** Cinacalcet and Conventional Therapy (n=1,948)

** Placebo and Conventional Therapy (n=1,935)

*  Follow-up: 5.25 years

* Primary outcome: Death or CV event

===Inclusion Criteria===<!-- remove when cleared by an editor -->

* >18 years of age

* Treated with maintenance hemodialysis 3 times a week for >=3mo

* PTH ≥ 300pg/mL (31.8 pmol/L)

* Ca ≥ 8.4 mg/dL (2.1 mmol/L)

* Ca * P ≥ 45mg²/dL² (3.63 mmol²/L²)

* Parathyroidectomy 12 weeks before date of informed consent

* Severe concomitant disease including life threatening malignancy or AIDS (life expectancy <5y) and other life threatening concomitant disease. Basal and squamous cell carcinoma of the skin could be included.

* Received therapy with cinacalcet within 3 months of randomization.

* Hospitalization within 12 weeks of randomization for any of: MI, unstable angina, heart failure, peripheral vascular disease, stroke

* Seizure within 12 weeks prior to randomization

* Age: 55.0y

* Sex: 41.5% female

** Diabetes, Type 1: 4%

** Diabetes, Type 2: 30%

Significant differences were reported between mean dBP (p=0.02) and TIA (P<0.05).

 

'''Biochemical'''

 

* Dialysis dose ≥1.2 spKt/V or ≥ 65 URR

* Serum (Ca*P)²: 63.2 mg/dL

==Interventions==<!-- remove when cleared by an editor -->

* All groups received conventional therapy:

** Prescribed at the discretion to the treating physicians encouraged to follow clinical practice guidelines

** 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

** Escalation based on PTH and serum Ca

''Presented as Cinacalcet vs Placebo''

''Cardiovascular event defined as: MI, unstable angina hospitalization, heart failure, peripheral vascular event''

: 48.2% vs. 49.2% (Relative HR=0.88 [CI 0.79-0.97]; p=0.008)

; Time to Death

: Relative HR=0.94 (p=0.249)

''After adjustment for baseline characteristics''

: Relative HR=0.86 (CI 0.78-0.96), P=0.006

===Secondary Outcomes===<!-- remove when cleared by an editor -->

'''Time to First Parathyroidectomy'''

Secondary endpoints of stroke, death from cardiovascular diseases and fractures were not statistically significant.

=== Lag Censoring Analysis ===<!-- remove when cleared by an editor -->

''Censoring of data at six months after study-drug discontinuation was performed''

; Time to Death or First Nonfatal Cardiovascular Event

: HR=0.85 (CI 0.76-0.95; P=0.003)

; Time to Death

: HR=0.83 (CI 0.73-0.96; P=0.009)<!-- remove when cleared by an editor -->

* Under the initial assumption of a 20% treatment effect, the presumed study power of 90% to 54% secondary to crossovers and drop-outs<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>

** 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>