Effect of Cinacalcet on Cardiovascular Disease in Patients Undergoing Dialysis

Santosh VarugheseSantosh 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 DesignInclusion 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 dailyDose escalation every 4 weeks for 20-weeks

60 mg, 90 mg, 120 mg, 180 mg daily

or every 8 weeksDepending 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 etcAssumptions:

Annual rate of 10 composite end point - 23.2% in placebo groupAnnual rate of loss to follow-up of 1%Annual rate of dropout of 10% - C groupAnnual 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

ResultResultss

22nd August, 2006 to 31st January, 2008

C P

C P

22.7%

Study Treatment

Median drug exposure - longer in cinacalcet group21.2 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 drug1207 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%) vsP: 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%) vsP: 718 of 1935 patients (37.10%)

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

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

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

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

Primary Composite End Point

C: 938 of 1948 patients (48.2%) vsP: 952 of 1935 patients (49.2%)

Relative hazard 0.93; 0.85 to 1.02; P = 0.11)

After adjustment for baseline characteristicsRelative 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 PointsStroke: 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 AnalysisCensoring of data at 6 months after drug discontinuation

Lag-Censoring AnalysisCensoring 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

`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 etcsuggest that cinacalcet may result in nominally significant

reductions inRisk 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