Effect of Cinacalcet on Cardiovascular Disease in Patients Undergoing Dialysis

Santosh Varughese

EValuation Of cinacalcet hydrochloride therapy to Lower cardioVascular Events (EVOLVE) trial

Hypothesis treatment with cinacalcet would reduce the risks of death and nonfatal cardiovascular events among patients with secondary hyperparathyroidism who were undergoing dialysis.

Study Design
Multicenter, prospective, randomized, double-blind, placebo-controlled trial

Global study ~ 500 sites in 22 countries

US, Canada, Argentina, Brazil, Mexico, Australia, Austria, Belgium, Denmark, France, Germany, Hungary, Ireland, Italy, Netherlands, Poland, Portugal, Russia, Spain, Sweden, Switzerland & UK

Randomization stratified according to country and diabetes status

Study Design
Inclusion Criteria
18 yr of age CKD 5 on HD / HDF three times a week for 3 months iPTH 300 pg/ml (31.8 pmol/L) Calcium (central lab) 8.4 mg/dL (2.1 mmol/L) Ca x P product 45 mg2/dl2 (3.63 mmol2/L2) Availablity for follow up Agree to be followed until the end of study Ethical - appropriate written informed consent obtained

Exclusion Criteria
Unstable medical condition Parathyroidectomy within 12 wks or anticipated within 6 months Life-limiting concomitant disease Therapy with cinacalcet within 3 months Hospitalization within 12 wk of randomization [MI, unstable angina, CHF (including any unplanned ultrafiltration), PVD, or CVA Seizure within 12 wk before randomization Scheduled date for living donor kidney transplantation General Other investigational procedures, other device / drug trial(s), sensitivity or intolerance, inability to give consent, pregnant, breast feeding, or of child-bearing potential & not using contraception

Study Intervention
Either cinacalcet or placebo @ 30 mg daily Dose escalation every 4 weeks for 20-weeks
60 mg, 90 mg, 120 mg, 180 mg daily

or every 8 weeks
Depending on levels of PTH and S. Calcium

Dialysis, PO4 binders, Vitamin D sterols, Ca supplements, and other medications continued

Schematic diagram of study design

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

End Points
Primary Composite End Point Time to death or Time to 1st nonfatal cardiovascular event MI, hospitalization for unstable angina, CHF or peripheral vascular event Secondary end points Time to the individual components of the primary composite end point Death from cardiovascular causes Stroke Bone fracture Parathyroidectomy

Sample size etc

Assumptions:
Annual rate of 10 composite end point - 23.2% in placebo group Annual rate of loss to follow-up of 1% Annual rate of dropout of 10% - C group Annual rate of drop-in of 10% - P group 20% treatment effect Power of 90% Sample size 3800

Overall event rate < 20.8% extended trial by 16 months

Intention to treat analysis

Results

22nd August, 2006 to 31st January, 2008

22.7%

Study Treatment
Median drug exposure - longer in cinacalcet group
21.2 months vs 17.5 months

Daily median dose

C 55 mg (10th 90th percentile,28 to 130) P 125 mg (10th 90th percentile, 43 to 161)

Maximum daily dose

P 80.0% vs C38.3%

Re-estimated statistical power = 54%

Observed rates of events, dropout and drop-in

P: Commercially cinacalcet before 10 event

384 of 1935 (19.8%) ~ annual rate 7.4%

C: Discontinuation of study drug

1207 of 1948 (62.0%) ~ annual rate 27.3%

Loss to follow up only 2.1%

Primary Composite End Point

Time to death or 1st nonfatal cardiovascular event MI, hospitalization for unstable angina, CHF or peripheral vascular event

Primary Composite End Point

C: 938 of 1948 patients (48.2%) vs P: 952 of 1935 patients (49.2%) Relative hazard 0.93; 0.85 to 1.02; P = 0.11)

C: 703 of 1948 patients (36.09%) vs P: 718 of 1935 patients (37.10%)

C: 187 of 1948 patients (9.6%) vs P: 183 of 1935 patients (9.5%)

C: 56 of 1948 patients (2.9%) vs P: 66 of 1935 patients (3.4%)

C: 206 of 1948 patients (10.6%) vs P: 236 of 1935 patients (12.2%)

C: 184 of 1948 patients (9.45%) vs P: 200 of 1935 patients (10.36%)

Primary Composite End Point

C: 938 of 1948 patients (48.2%) vs P: 952 of 1935 patients (49.2%) Relative hazard 0.93; 0.85 to 1.02; P = 0.11) After adjustment for baseline characteristics Relative hazard 0.88 (95% CI, 0.79 - 0.97; P = 0.008) Relative hazard for DEATH 0.86 (0.78 to 0.96; P = 0.006)

Secondary End Points

Stroke: C 115 vs P 102 (relative hazard 1.07; 0.82 to 1.40; P = 0.61) Death from CV causes: C 377 vs P 391 (relative hazard 0.92; 0.80 to 1.07; P = 0.28). Parathyroidectomy: C140 (7%) vs P 278 (14%) (relative hazard 0.44, 0.36 to 0.54)

Fracture: C 238 (12%) vs P 255 (13%) (relative hazard 0.89, 0.75 to 1.07)

Multiple CV events
Cumulative event rates for 10 composite end point C 25.3 (24.1 to 26.5) per 100 pt-years P 27.3 (26.0 to 28.5) per 100 pt-years (P = 0.02).

Lag-Censoring Analysis
Censoring of data at 6 months after drug discontinuation

Lag-Censoring Analysis
Censoring of data at 6 months after drug discontinuation 10 composite end point C: 638 vs P: 658 (relative hazard, 0.85; 95% CI, 0.76 to 0.95; P = 0.003)
Primary Composite End Point
Time to death or 1st nonfatal cardiovascular event

Other Sensitivity Analyses

Censoring for kidney transplantation, parathyroidectomy or use of commercially available cinacalcet Relative hazards : 10 composite end point were 0.90 (0.82 to 0.99; P = 0.03)

Censoring at time of any events Relative hazard: of 0.84 (0.76 to 0.93; P<0.001)

Inverse Probability of Censoring Weight

Crossover & discontinuation of drug prior to event or ending study Data split into time intervals from randomization until event, discontinued drug or completed study, whichever occurred first Probability of continuing to receive study drug at end of each time interval

Inverse Probability of Censoring Weight

Relative hazard for 10 composite endpoint 0.77 (95% CI 0.66 to 0.88)

`
C P

Adverse Events
Drug discontinuation due to adverse events C 18.1% vs P 13% Serious adverse event rates similar Neoplastic events
C115 vs P 90 patients i.e. 2.9 & 2.5 events/100 patient-years

Fatal: C 25 vs P 23

Discussion
Observational studies
Increased risks of death & CV events with PTH > 600 pg/ml Mixed results - U-shaped, null, or inverse associations
No RCT - lowering PTH reduces mortality, CV events or other major CKD-MBD complications

EVOLVE study
Nonsignificant 7% in risk of 10 composite end point with cinacalcet nondefinitive After adjustment for baseline characteristics nominally significant 12% risk reduction

Discussion
Cinacalcet reduced the rate of parathyroidectomy by more than half Parathyroidectomy varied widely according to age, sex & region Lowest in the United States & among the elderly

Discussion
Parathyroidectomy varied widely according to age, sex & region Lowest in the United States & among the elderly Severe unremitting HPT endpoint (any one) Plasma PTH >1000 pg/mL (106.0 pmol/L) + S. Ca >10.5 mg/dL (2.6 mmol/L) on two consecutive occasions Plasma PTH >1000 pg/mL (106.0 pmol/L) + S. Ca >10.5 mg/dL (2.6 mmol/L) on one occasion with prescription of commercial cinacalcet within 2 months Surgical parathyroidectomy

Severe unremitting HPT endpoint

Strengths
Large number Patients from many geographic regions Diversity of age, race & ethnic group Continued active CKD-MBD therapy [PO4 binders & vitamin D sterols] Continued antihypertensive, antiplatelet & lipid-lowering agents All cardiovascular end points independently studied Relatively few patients lost to follow-up

Limitations
Lower-than-anticipated event rate prolongation of follow-up time High rate of dropout -- trial fatigue, GI side effects, etc More Cinacalcet patients dropped out because of adverse effects

Commercial cinacalcet ~ one in five patients in placebo group

Baseline imbalances between randomized groups
including a 1-year difference in age

Ambitious expected reduction in event rate (20%) between groups

Authors Conclusions
Adjusting for baseline characteristics or accounting for
parathyroidectomy, kidney transplantation etc suggest that cinacalcet may result in nominally significant reductions in Risk of death or first MI, hospitalization for unstable angina, CHF or peripheral vascular event Relative reduction: 10-15%; Absolute reduction: 2-3%

Pre-specified unadjusted intention-to-treat analysis Cinacalcet did not significantly reduce risk of death or major cardiovascular events

My Conclusions
Cinacalcet did not significantly reduce risk of death or major cardiovascular events Expected biochemical improvement seen

Watch out for GI side-effects, hypocalcemia & ?? Seizures

? Signal towards benefit in age 65 years ? Beneficial in perventing calciphylaxis