EVOVLE Trial

Sandeep G Huilgol

• Effect of Cinacalcet on Cardiovascular Disease in Patients Undergoing Dialysis

• Dr. Glenn M. Chertow et al N Engl J Med 2012;367:2482-94.

Background

• Disorders of mineral metabolism- extraskeletal (including vascular) calcification among patients with chronic kidney disease.

• It has been hypothesized that treatment with the calcimimetic agent cinacalcet might reduce the risk of death or nonfatal cardiovascular events in such patients.

Rationale behind the trial

1. Various biochemical abnormalities in sHPT are associated with increased mortality.

2. Cinacalcet decreases the levels of PTH,P and Ca X P which are associated with increased mortality.

Associations between elevations in phosphorus, calcium, calcium-phosphorus product, and parathyroid hormone (PTH) with risk for mortality.

Chertow G M et al. CJASN 2007;2:898-905

©2007 by American Society of Nephrology

Effect of cinacalcet on PTH, Ca, P, and Ca × P in phase 3 clinical trials (21,22).

Chertow G M et al. CJASN 2007;2:898-905

©2007 by American Society of Nephrology

Calcimimetics : Definition• Calcimimetic agents are small organic molecules that act

as allostersic activators of the calcium sensing receptors (CaSR) in the parathyroid gland and other tissues.

• Calcimimetics increase the threshold sensitivity of the

CaSR to extracellular calcium leading to activation of the CaSR at lower than normal levels of serum calcium.

• As a result, in the presence of these agents, even the low levels of ionized calcium typically present in patients with chronic kidney disease exert a suppressive effect on PTH secretion

Molecular targets regulating parathyroid gland function include, in rank order of importance, CASR, VDR, and a hypothetical phosphate sensing

mechanism

• CASR is the major regulator of PTH transcription, secretion, and parathyroid gland hyperplasia.

• VDR, which affects PTH transcription but not PTH secretion, may have a subordinate physiologic role to calcium in regulating parathyroid gland function.

For example:

• Secondary hyperparathyroidism and bone abnormalities in VDR-deficient mice can be corrected by normalizing serum calcium concentrations, whereas

• Hyperparathyroidism in CASR-deficient mice cannot be corrected by elevated 1,25(OH)2D3.

Study Design• Multicenter, prospective, randomized, placebo-

controlled trial, • Compared cinacalcet with placebo in 3883 adults

undergoing dialysis.• All the patients were eligible to receive conventional

therapy, including phosphate binders, vitamin D sterols, or both.

• Randomization was stratified according to country and diabetes status with the use of fixed blocks.

• The sponsor, investigators, and patients were unaware of the treatment assignments

Study Intervention

• Patients received either cinacalcet or placebo at a starting dose of 30 mg daily.

• Patients were eligible for dose escalation once every 4 weeks during a 20-week escalation phase (to 60 mg, 90 mg, 120 mg, or 180 mg daily) or every 8 weeks during follow-up, depending on levels of plasma parathyroid hormone and serum calcium.

Study End Points

• The primary composite end point was the time to death or the first nonfatal cardiovascular event (myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event.

• Secondary end points included the time to the individual components of the primary composite end point, death from cardiovascular causes, stroke, bone fracture, and parathyroidectomy.

Schematic diagram of the Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) study design.

Chertow G M et al. CJASN 2007;2:898-905

©2007 by American Society of Nephrology