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EVOLVE TRIAL

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  • 1. EVOVLE Trial Sandeep G Huilgol
  • 2. • Effect of Cinacalcet on Cardiovascular Disease in Patients Undergoing Dialysis • Dr. Glenn M. Chertow et al N Engl J Med 2012;367:2482-94.
  • 3. 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.
  • 4. 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.
  • 5. 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
  • 6. 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
  • 7. 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
  • 8. Molecular targets regulating parathyroid gland function include, in rank order of importance, CASR, VDR, and a hypothetical phosphate sensing mechanism
  • 9. • 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.
  • 10. 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
  • 11. 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.
  • 12. 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.
  • 13. 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