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ACC 14 WashingtonTomás Ripoll

Almudena Castro

Antoni Martínez

Alfonso Varela

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• Diabetes– ALECARDIO– STAMPADE

• Lípidos– LAPLACE-2

– GAUSS-2

• C.I Crónica– STABILTY

#postACC14JAMA. Published online March 30, 2014. doi:10.1001/jama.2014.3321

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Aleglitazar in ACS and T2DM

Study Hypothesis:Study Hypothesis:

Aleglitazar, added to standard of care of pts with T2DM and recent Aleglitazar, added to standard of care of pts with T2DM and recent acute coronary syndrome (ACS), would reduce cardiovascular acute coronary syndrome (ACS), would reduce cardiovascular mortality and morbiditymortality and morbidity. .

phase 3 phase 3

superiority trialsuperiority trial

randomized, placebo-controlled, double-blind, multicenterrandomized, placebo-controlled, double-blind, multicenter

JAMA. Published online March 30, 2014. doi:10.1001/jama.2014.3321

#postACC14JAMA. Published online March 30, 2014. doi:10.1001/jama.2014.3321

Inclusion and Exclusion Criteria

Hospitalized with ACS (STEMI, NSTEMI, Hospitalized with ACS (STEMI, NSTEMI, or UA)or UA)

Type 2 DM (managed by diet or Type 2 DM (managed by diet or medication)medication)

Patients could be randomized at:Patients could be randomized at:

• hospital discharge for index ACS hospital discharge for index ACS

• after screening period of up to 12 wks to after screening period of up to 12 wks to allow clinical stabilization, completion of allow clinical stabilization, completion of planned revascularization, achievement planned revascularization, achievement of steady state renal function. of steady state renal function.

x Heart failure – Class II-IVHeart failure – Class II-IV

x Heart failure hospitalization inHeart failure hospitalization in

prior 12 monthsprior 12 months

x Severe peripheral edemaSevere peripheral edema

x CKD - eGFR <45 ml/min-1.73 mCKD - eGFR <45 ml/min-1.73 m22

x Fasting triglycerides > 400 mg/dLFasting triglycerides > 400 mg/dL

x Ongoing Rx with fibrate or TZDOngoing Rx with fibrate or TZD

x Liver diseaseLiver disease

x Anemia – Hgb <10 mg/dLAnemia – Hgb <10 mg/dL

#postACC14JAMA. Published online March 30, 2014. doi:10.1001/jama.2014.3321

PrimaryPrimary• Time to CV death, non-fatal MI, non-fatal strokeTime to CV death, non-fatal MI, non-fatal stroke

SecondarySecondary• Time to CV death, non-fatal MI, non-fatal stroke, hosp for UATime to CV death, non-fatal MI, non-fatal stroke, hosp for UA• Time to all-cause death, non-fatal MI, non-fatal strokeTime to all-cause death, non-fatal MI, non-fatal stroke• Time to unplanned coronary revascularizationTime to unplanned coronary revascularization

ExploratoryExploratory• Glycemic controlGlycemic control• Changes in lipid levelsChanges in lipid levels

SafetySafety• Hospitalization due to heart failureHospitalization due to heart failure• Renal safety composite – (ESRD, doubling SCr, 50% increase in SCr leading Renal safety composite – (ESRD, doubling SCr, 50% increase in SCr leading

to study drug D/C)to study drug D/C)• AEs of special interest – fluid retention, edema, weight, bone fx, AEs of special interest – fluid retention, edema, weight, bone fx,

hypoglycemia, malignancieshypoglycemia, malignancies

#postACC14JAMA. Published online March 30, 2014. doi:10.1001/jama.2014.3321

Type 2 DM and recent Acute Coronary SyndromeType 2 DM and recent Acute Coronary Syndrome(STEMI, NSTEMI or UA)(STEMI, NSTEMI or UA)

AleglitazarAleglitazar150 150 µµg/day in morningg/day in morning

PlaceboPlacebo

Event Driven – 950 positively-adjudicated 1Event Driven – 950 positively-adjudicated 1oo Endpoint events Endpoint eventsAnticipated ~2.5 years follow-upAnticipated ~2.5 years follow-up

N ~ 7000 Patients RandomizedN ~ 7000 Patients RandomizedDouble blind, 1:1 RatioDouble blind, 1:1 Ratio

Up to 12 weeks after index eventUp to 12 weeks after index event

Study visits: 1, 3, 6, 9, 12 mos, then alternative visits and phone q3 mosStudy visits: 1, 3, 6, 9, 12 mos, then alternative visits and phone q3 mos

#postACC14JAMA. Published online March 30, 2014. doi:10.1001/jama.2014.3321

Data Safety Monitoring BoardEarly Termination of Trial

• DSMB recommended termination of trial for futilityDSMB recommended termination of trial for futility

• Exec Committee and Sponsor agreed – trial terminated July 2013Exec Committee and Sponsor agreed – trial terminated July 2013

Finalization of trial database on December 17, 2013:Finalization of trial database on December 17, 2013:

704 adjudicated primary endpoint events – 74% of predicted704 adjudicated primary endpoint events – 74% of predicted

Median follow-up – 104 weeks (IQR 82-129)Median follow-up – 104 weeks (IQR 82-129)

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Primary Efficacy Endpoint

PlaceboPlacebo 36103610 33943394 32523252 27202720 17061706 773773 118118AleglitazarAleglitazar 36163616 33873387 32493249 27312731 16881688 780780 101101

No. at risk:No. at risk:

HR = 0.96 (95% CI, 0.83-1.11)p = 0.57

Cardiovascular Death, Non-Fatal MI, Non-Fatal Stroke

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Mean value at baseline, (mg/dL)Placebo: 41.8Aleglitazar: 42.2

Mean value at baseline, (mg/dL)Placebo: 41.8Aleglitazar: 42.2

Mean value at baseline, (mg/dL)Placebo: 154Aleglitazar: 152

Mean value at baseline, (mg/dL)Placebo: 154Aleglitazar: 152

Mean value at baseline, (mg/dL)Placebo: 79.7Aleglitazar: 78.9

Mean value at baseline, (mg/dL)Placebo: 79.7Aleglitazar: 78.9

Mean value at baseline, (%)Placebo: 7.8Aleglitazar: 7.8

Mean value at baseline, (%)Placebo: 7.8Aleglitazar: 7.8

HbA1CHbA1C

TriglyceridesTriglycerides

HDL-CHDL-C

LDL-CLDL-C

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HR = 1.22 (95% CI, 0.94-1.59)p = 0.14

Heart Failure Serious Adverse Event: Heart Failure Serious Adverse Event: Aleglitazar 4.7% vs Placebo 3.8%, HR Aleglitazar 4.7% vs Placebo 3.8%, HR 1.24; 95% CI 0.99 to 1.66, P = 0.06 1.24; 95% CI 0.99 to 1.66, P = 0.06

Hospitalization for Heart Failure

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Change in Creatinine

Composite Renal Endpoint: Composite Renal Endpoint: Aleglitazar 7.4% vs Placebo 2.7%, HR Aleglitazar 7.4% vs Placebo 2.7%, HR 2.85; 95% CI 2.85; 95% CI 2.25 to 3.60; P <0.0012.25 to 3.60; P <0.001

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Gastrointestinal Hemorrhage

Hazard Ratio 1.44; (95% CI, 1.03 - 2.00)Log-rank P = 0.03

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Discusión: ¿ es la HA1C un marcador de riesgo de complicacionesMacrovasculares?

#postACC14DOI: 10.1056/NEJMoa1401329

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STAMPADE

DOI: 10.1056/NEJMoa1401329

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STAMPADE

DOI: 10.1056/NEJMoa1401329

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STAMPADEDiscusión:Cirugía bariátrica DM2: ¿ más costeefectiva que otros procedimientosinvasivos que tratan factores de riesgo cardiovascular?

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Discusión: Cardiopatía isquémica estable con TMO difícil encontrar disminución de eventos con fármacos nuevos

#postACC14 10.1016/j.jacc.2014.03.019

The LAPLACE-2 Study

LDL-C Assessment with PCSK9 MonoclonaL Antibody Inhibition Combined With Statin ThErapy – 2 (NCT01763866)

Design: A 12-week, randomized, double-blind, placebo- and ezetimibe- controlled, phase III study Objective: To evaluate the efficacy and safety of evolocumab administered biweekly (140 mg) or monthly (420 mg) in combination with a statin in hypercholesterolemic patients

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The LAPLACE-2 Study

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The LAPLACE-2 Study

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The LAPLACE-2 Study

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The LAPLACE-2 Study

Conclusiones:

1) The combination of evolocumab and a statin significantly lowered LDL-C levels in patients with hypercholesterolemia compared:

1. to statin therapy with ezetimibe (P<0.001) 2. or statin therapy alone (P<0.001).

2) Evolocumab 140 mg Q2W and 420 mg QM dosing were clinically equivalent.

#postACC14 10.1016/j.jacc.2014.03.019

Question to answer: Does monotherapy with evolocumab every 2 weeks (Q2W) or every month (QM) effectively lower LDL-C in statin-intolerant patients with hypercholesterolemia when compared with ezetimibe?

GAUSS-2

#postACC14 10.1016/j.jacc.2014.03.019

GAUSS-2Objetivo Primario:1)% cambio LDL-C basal a semana 10-122) % cambio LDL-C basal a semana 12

Monotherapy with evolocumab significantly lowered LDL-C levels in statin-intolerant patients with hypercholesterolemia compared to treatment with ezetimibe.

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Discusión:1) Otro fármaco más que mejora los perfiles analíticos o servirá para disminuir eventos clínicos.… A la espera de estudio FOURIER

2) ¿ Hasta cuánto hay que disminuir el LDL?