EVOLVE

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Chertow GM, et al. "Effect of Cinacalcet on Cardiovascular Disease in Patients Undergoing Dialysis". The New England Journal of Medicine. 2012. 367(26):2482-2494.
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Clinical Question

Among ESRD patients undergoing hemodialysis, does cinacalcet reduce the rate of death or CV events?

Bottom Line

Cinacalcet did not reduce rates of death and cardiovascular events among ESRD patients receiving hemodialysis.

Major Points

Secondary hyperparathyroidism is a risk factor for cardiovascular disease among patients with CKD, possibly mediated by increased arterial stiffness and LV hypertrophy.[1][2] Cinacalcet is a calcimimetic agent that primarily acts as an allosteric modulator of the calcium sensing receptor (CaSR) to reduce serum PTH, calcium, and phosphorus levels and possibly inhibit vascular calcification.[3] Cinacalcet and other calcimimetics have been widely used for these benefits, but whether these effects would impact rates of CV events among ESRD patients was unknown.

Published in 2012, the Evaluation of Cinacalcet Hydrochloride 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-center, international, blinded, randomized controlled trial enrolled 3,883 patients. and randomized patients to either cinacalcet or placebo. Drug doses were increased 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 physician. After an unspecified follow-up period of up to about 5 years, there was no difference in rates of the primary outcome in the cinacalcet group (48.2%) compared to the placebo group (49.2%). In 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. 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[4]. 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.

Controversy exists on how these adjusted analyses should be interpreted, and some consider the outcomes of this trial to be inconclusive.[5] The KDIGO recommendations on the use of cinacalcet did not change following the publication of this trial.[6]

Guidelines

KDIGO CKD-BMD (2009, adapted)[7]

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.[6]

  • 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).

Design

  • Multicenter, multinational randomized control trial[8][9]
  • N=3,883 patients with ESRD
    • Cinacalcet (n=1,948)
    • Placebo (n=1,935)
  • Follow-up: Up to 5.25 years
  • Analysis: Intention-to-treat
  • Primary outcome: Composite of death or CV event

Population

Inclusion Criteria

  • Age ≥18 years
  • Maintenance hemodialysis 3 times a week for ≥3 months
  • PTH ≥300 pg/mL (31.8 pmol/L)
  • Ca ≥8.4 mg/dL (2.1 mmol/L)
  • Ca × P ≥45mg²/dL² (3.63 mmol²/L²)

Exclusion Criteria

  • Parathyroidectomy ≤12 weeks prior to informed consent
  • Severe concomitant disease
  • Received therapy with cinacalcet ≤3 months of randomization.
  • Hospitalization ≤12 weeks of randomization for any of: MI, unstable angina, heart failure, peripheral vascular disease, stroke
  • Seizure ≤12 weeks prior to randomization
  • Scheduled date for kidney transplant from known living donor
  • Anticipated parathyroidectomy within 6 months after randomization

Baseline Characteristics

Significant differences were reported between mean diastolic BP and prior TIA rate.

Demographics

From the cinacalcet group.

  • Age (mean): 55 years
  • Female: 42%
  • Race: 58% white, 21% black, 21% other
  • BMI (mean): 26
  • Dialysis vintage (duration): 45 months
  • Blood pressure: 140/80
  • Medical history:
    • Diabetes mellitus: 34% (T2DM in 30%)
    • Cardiovascular disease: 95%
      • Hypertension: 93%
      • Heart failure: 23%
      • Peripheral vascular disease: 16%
      • CABG: 7%
      • PCI: 7%
      • MI: 12%
      • TIA: 5%
      • Amputation: 6%
      • Atrial fibrillation: 10%

Biochemical

  • Hemoglobin: 11.8 g/dL
  • BUN: 61.9 mg/dL
  • Creatinine: 10.1 mg/dL
  • Dialysis dose ≥1.2 spKt/V or ≥65 URR: 85.1%
  • Serum calcium: 9.8 mg/dL
  • Serum phospohorus: 6.5 mg/dL
  • Serum Ca × P: 63.2 mg²/dL²
  • Serum potassium: 5.1 mEq/L
  • PTH: 691.8 pg/mL

Interventions

  • Randomization by blocks according to country and diabetes status
  • All groups received conventional therapy consisting of:
    • Dialysis, phosphate binders, vitamin D sterols, calcium supplements, other medications
    • These were administered at the discretion of the treating physicians, who were encouraged to follow clinical practice guidelines
  • Cinacalcet group received:
    • Starting dose of 30 mg/d
    • Eligible for dose escalation once every 4 weeks during a 20 week escalation phase, or every 8 weeks during followup
    • Dose escalated to achieve PTH <300 pg/mL and calcium <8 mg/dL
  • Placebo group received same doses and dosing protocol as treatment group

Outcomes

Comparisons are cinacalcet vs. placebo.

Primary Outcome

Time to death or first nonfatal CV event
48.2% vs. 49.2% (HR 0.93; 95% CI 0.85-1.02; P=0.11)
After adjustment for baseline characteristics: HR 0.88 (95% CI 0.79-0.97; P=0.008)

Secondary Outcomes

Time to death
After adjustment for baseline characteristics: HR 0.86 (95% CI 0.78-0.96; P=0.006)
Stroke
HR 1.07 (95% CI 0.82-1.40; P=0.61)
Death from CV causes
HR 0.92 (95% CI 0.80-1.07; P=0.28)
Time to parathyroidectomy
HR 0.44 (CI 0.36-0.54); p<0.001
Fracture
12% vs. 13% (HR 0.89; 95% CI 0.75-1.07)
After adjustment for baseline characteristics: HR 0.85 (95% CI 0.71-1.01)

Lag-Censoring Analysis

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

Time to death or first nonfatal CV event
638 vs. 658 events (HR 0.85; 95% CI 0.76-0.95; P=0.003)
Time to death
HR 0.83 (95% CI 0.73-0.96; P=0.009)

Adverse Events

Any AE
93% vs. 91% (P<0.001)
Serious AEs
69% vs. 70%
Treatment-related serious AEs
3.6% vs. 2.3% (P=0.049)
Convulsions
2.5% vs. 0.8%
Hypocalcemia
12.4% vs. 1.7% (P<0.001)
Hypersensitivity reaction
9.4% vs. 8.3%
Nervous system disorder
36.7% vs. 30.5% (P<0.001)
Nausea
29.1% vs. 15.5% (P<0.001)
Vomiting
25.6% vs. 13.7% (P<0.001)
Diarrhea
20.5% vs. 18.7%

Criticisms

  • Age-adjusted HR results in statistically significant results for primary outcome, but was not defined as the primary endpoint
    • Patients one year older in cinacalcet group; older age known to increase mortality in dialysis patients
  • 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 crossover (use of commercial cinacalcet) in placebo group (19.8%)
  • Under the initial assumption of a 20% treatment effect, the presumed study power of 90% to 54% secondary to crossovers and drop-outs[4]
  • Combination of atherosclerotic and non-atherosclerotic cardiovascular endpoints
    • Cinacalcet hypothesized to primarily effect non-atherosclerotic endpoints (slowing arterial calcification, reducing myocardial calcium accumulation)[10]

Funding

  • Amgen (the manufacturer of Cinacalcet) was significantly involved.

Further Reading

  1. Chertow GM, et al. "Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE): Rationale and Design Overview." CJASN. 2007;2:898-905.
  2. Torres PA, Broe MD. "Calcium-sensing receptor, calcimimetics, and cardiovascular calcifications in chronic kidney disease." Kidney International. 2012;82:19-25.
  3. Byrnes CA, Shepler BM. "Cinacalcet: A New Treatment for Secondary Hyperparathyroidism in Patients Receiving Hemodialysis." Pharmacotherapy. 2005;25(5):709–716.
  4. 4.0 4.1 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.
  5. 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).
  6. 6.0 6.1 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.
  7. 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.
  8. Chertow GM, et al. Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE): rationale and design overview. Clin J Am Soc Nephrol. 2007 Sep;2(5):898-905.
  9. Chertow GM, et al. Baseline characteristics of subjects enrolled in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial. Nephrol Dial Transplant. 2012 Jul;27(7):2872-9.
  10. 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.