Aleglitazar study for diabetes and ACS stopped early due to futility
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Ponencia sobre 'Diabetes, lípidos y cardiopatía isquémica crónica’, presentada por la Dra. Almudena Castro en el directo online 'Lo mejor del ACC 2014', celebrado en la Casa del Corazón.
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Aleglitazar study for diabetes and ACS stopped early due to futility
- 1. #postACC14 ACC 14 Washington Tomás Ripoll Almudena Castro Antoni Martínez Alfonso Varela
- 2. #postACC14 • Diabetes – ALECARDIO – STAMPADE • Lípidos – LAPLACE-2 – GAUSS-2 • C.I Crónica – STABILTY
- 3. #postACC14 JAMA. Published online March 30, 2014. doi:10.1001/jama.2014.3321
- 4. #postACC14 Aleglitazar in ACS and T2DM Study Hypothesis:Study Hypothesis: Aleglitazar, added to standard of care of pts with T2DM and recentAleglitazar, added to standard of care of pts with T2DM and recent acute coronary syndrome (ACS), would reduce cardiovascularacute coronary syndrome (ACS), would reduce cardiovascular mortality and morbiditymortality and morbidity.. phase 3phase 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
- 5. #postACC14 JAMA. 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 orType 2 DM (managed by diet or medication)medication) Patients could be randomized at:Patients could be randomized at: • hospital discharge for index ACShospital discharge for index ACS • after screening period of up to 12 wks toafter screening period of up to 12 wks to allow clinical stabilization, completion ofallow clinical stabilization, completion of planned revascularization, achievementplanned 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
- 6. #postACC14 JAMA. 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 leadingRenal 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
- 7. #postACC14 JAMA. 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) AleglitazarAleglitazar 150150 µµg/day in morningg/day in morning PlaceboPlacebo Event Driven – 950 positively-adjudicated 1Event Driven – 950 positively-adjudicated 1oo Endpoint eventsEndpoint events Anticipated ~2.5 years follow-upAnticipated ~2.5 years follow-up N ~ 7000 Patients RandomizedN ~ 7000 Patients Randomized Double 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
- 8. #postACC14 JAMA. Published online March 30, 2014. doi:10.1001/jama.2014.3321 Data Safety Monitoring Board Early 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)
- 9. #postACC14 Primary Efficacy Endpoint PlaceboPlacebo 36103610 33943394 32523252 27202720 17061706 773773 118118 AleglitazarAleglitazar 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
- 10. #postACC14 Mean value at baseline, (mg/dL) Placebo: 41.8 Aleglitazar: 42.2 Mean value at baseline, (mg/dL) Placebo: 41.8 Aleglitazar: 42.2 Mean value at baseline, (mg/dL) Placebo: 154 Aleglitazar: 152 Mean value at baseline, (mg/dL) Placebo: 154 Aleglitazar: 152 Mean value at baseline, (mg/dL) Placebo: 79.7 Aleglitazar: 78.9 Mean value at baseline, (mg/dL) Placebo: 79.7 Aleglitazar: 78.9 Mean value at baseline, (%) Placebo: 7.8 Aleglitazar: 7.8 Mean value at baseline, (%) Placebo: 7.8 Aleglitazar: 7.8 HbA1CHbA1C TriglyceridesTriglycerides HDL-CHDL-C LDL-CLDL-C
- 11. #postACC14 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%, HRAleglitazar 4.7% vs Placebo 3.8%, HR 1.24; 95% CI 0.99 to 1.66, P = 0.061.24; 95% CI 0.99 to 1.66, P = 0.06 Hospitalization for Heart Failure
- 12. #postACC14 Change in Creatinine Composite Renal Endpoint:Composite Renal Endpoint: Aleglitazar 7.4% vs Placebo 2.7%, HRAleglitazar 7.4% vs Placebo 2.7%, HR 2.85; 95% CI2.85; 95% CI 2.25 to 3.60; P <0.0012.25 to 3.60; P <0.001
- 13. #postACC14 Gastrointestinal Hemorrhage Hazard Ratio 1.44; (95% CI, 1.03 - 2.00) Log-rank P = 0.03
- 14. #postACC14 Discusión: ¿ es la HA1C un marcador de riesgo de complicaciones Macrovasculares?
- 16. #postACC14
- 19. #postACC14 STAMPADEDiscusión: Cirugía bariátrica DM2: ¿ más coste efectiva que otros procedimientos invasivos que tratan factores de riesgo cardiovascular?
- 20. #postACC14
- 21. #postACC14
- 22. #postACC14
- 23. #postACC14
- 24. #postACC14
- 25. #postACC14 Discusión: Cardiopatía isquémica estable con TMO difícil encontrar disminución de eventos con fármacos nuevos
- 26. #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
- 30. #postACC14 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.
- 31. #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
- 32. #postACC14 10.1016/j.jacc.2014.03.019 GAUSS-2 Objetivo Primario: 1)% cambio LDL-C basal a semana 10-12 2) % 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.
- 33. #postACC14 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?
Notas del editor
- Randomized, double-blind, ezetimibe-controlled, multicenter clinical trial; N=307 Randomization: 1 of 4 arms comparing evolocumab (140 mg SC§ Q2W or 420 mg SC QM) + placebo (PBO) PO QD vs ezetimibe 10 mg PO QD + placebo (SC Q2W or SC QM)
- The combination of evolocumab and a statin significantly lowered LDL-C levels in patients with hypercholesterolemia compared to statin therapy with ezetimibe (P&lt;0.001) or statin therapy alone (P&lt;0.001). Evolocumab 140 mg Q2W and 420 mg QM dosing were clinically equivalent.
- Randomized, double-blind, ezetimibe-controlled, multicenter clinical trial; N=307 Randomization: 1 of 4 arms comparing evolocumab (140 mg SC§ Q2W or 420 mg SC QM) + placebo (PBO) PO QD vs ezetimibe 10 mg PO QD + placebo (SC Q2W or SC QM)