LO MEJOR DE EL ACC.16 CARDIOMETABOLICO

Transcription

1 LO MEJOR DE EL ACC.16 CARDIOMETABOLICO RICARDO GÓMEZ PALÁU INTERNISTA CARDIOLOGO U. Javeriana U. El Bosque Clinica SHAIO

2 AGENDA HOPE 3 TRIAL. GAUSS 3 TRIAL. ACCELERATE TRIAL.

3 NO CONFLICTOS DE INTERES

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6 Intermediate-Risk Population Inclusion Criteria (Target Risk 1.0%/yr) W ome 60yrs,me 55 yrs with at least one additional Risk Factor Increased WHR Smoking Low HDL-C Dysglycemia Mild renal dysfunction Family history of CHD Exclusion Criteria: CVD or indication(s) or contraindication(s) to study drugs No strict BP or LDL-C criteria for entry Uncertainty principle 5

7 The HOPE-3 Trial 228 centers in 21 countries Coordinated by PHRI, Hamilton, Canada Argentina, Australia, Brazil, Canada, China, Colombia, Czech Republic, Ecuador, Hungary, India, Israel, Korea, Malaysia, Netherlands, Philippines, Russia, Slovakia, South Africa, Sweden, United Kingdom, Ukraine 6

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10 Baseline Characteristics 12,705 randomized Age (yrs) 66 Female 46% Blood Pressure (mmhg) 138/82 LDL-Cholesterol (mg/dl) 128 LDL-Cholesterol (mmol/l) 3.3 Elevated waist-to-hip ratio 87% hscrp (g/l) median 2.0 Ethnicity White Caucasian Latin American Chinese Other Asian Black African 20% 28% 29% 20% 2% 11

11 BP Lowering vs. Placebo Outcome Cand+HCTZ N=6356 Placebo N=6349 HR (95% CI) Co-Primary (4.1%) 279 (4.4%) 0.93 ( ) 0.40 Co-Primary (4.9%) 328 (5.2%) 0.95 ( ) 0.51 Secondary 335 (5.3%) 364 (5.7%) 0.92 ( ) 0.26 CV Death 155 (2.4%) 170 (2.7%) 0.91 ( ) 0.40 MI 52 (0.8%) 62 (1.0%) 0.84 ( ) 0.34 Stroke 75 (1.2%) 94 (1.5%) 0.80 ( ) 0.14 CV Hosp. 319 (5.0%) 331 (5.2%) 0.96 ( ) 0.63 p 13

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16 Cholesterol Lowering: Outcomes Outcome Rosuvastatin N (%) Placebo N (%) HR (95% CI) p Co-Primary (3.7) 304 (4.8) 0.76 ( ) Co-Primary (4.4) 363 (5.7) 0.75 ( ) Secondary 1 306(4.8) 393 (6.2) 0.77 ( ) CV Death 154 (2.4) 171 (2.7) 0.89 ( ) 0.31 MI 45 (0.7) 69 (1.1) 0.65 ( ) 0.02 Stroke 70 (1.1) 99 (1.6) 0.70 ( ) 0.02 CV Hosp. 281 (4.4) 369 (5.8) 0.75 ( )

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18 Cholesterol Lowering: Safety Rosuvastatin N (%) Placebo N (%) Permanent Discontinuation 1510 (23.7) 1664 (26.2) Rhabdomyolysis/Myopathy 2 (0) 1 (0) 1.0 Muscle pain/ weakness 367 (5.8) 296 (4.7) Cataract Surgery 241 (3.8) 194 (3.1) 0.02 New Diabetes 232 (3.9) 226 (3.8) 0.82 p 24

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22 Combination vs Double Placebo Outcome Double Active N=3,180 N (%) Double Placebo N=3,168 N (%) HR (95% CI) p Co-Primary (3.6) 157 (5.0) 0.71 (0.56, 0.90) Co-Primary (4.3) 187 (5.9) 0.72 (0.57, 0.89) Secondary (4.6) 205 (6.5) 0.71 (0.57, 0.87) CV Death 75 (2.4) 91 (2.9) 0.82 ( ) 0.19 MI 21 (0.7) 38 (1.2) 0.55 ( ) Stroke 31 (1.0) 55 (1.7) 0.56 ( ) CV Hosp 141(4.4) 191 (6.0) 0.73 ( )

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29 The GAUSS-3 Trial Goal Achievement after Utilizing an anti-pcsk9 antibody in Statin Intolerant Subjects-3 Steven E. Nissen MD MACC* Erik Stroes MD PhD *Disclosure Study Sponsor: Amgen Consulting: Many pharmaceutical companies Clinical Trials: Amgen, AstraZeneca, Cerenis, Eli Lilly, Novartis, Novo Nordisk, The Medicines Company, Orexigen, Takeda, and Pfizer. Companies are directed to pay any honoraria, speaking or consulting fees directly to charity so that neither income nor tax deduction is received.

30 FUNDAMENTO 5-10 % pacientes alto riesgo CV suspenden estatinas después de experimentar síntomas musculares. Diagnostico se basa en la queja subjetiva, sin presencia de elevación enzimática. Estudio diseñado para evaluar intolerancia a estatinas.

31 CRITERIOS DE INCLUSION Incapacidad de tolerar Atorvastatina 10 mg u otra estatina. 3 o más estatinas, una de ellas en la menor dosis.

32 Study Design: Two Double-Blind Phases Phase A 511 patients enrolled at 53 centers with a history of intolerance to multiple statins due to muscle-related adverse effects. 10 weeks Atorvastatin 20 mg Placebo 10 weeks Atorvastatin 20 mg Placebo Phase B Patients proceeded to Phase B only if they had intolerable muscle symptoms o atorvastati,but otp acebo,orck 10xULN duri gpriorstati treatme t weeks Monthly SC evolocumab 420 mg Daily oral ezetimibe 10 mg

33 Selected Baseline Characteristics Characteristic Phase A (n=491) Phase B (n=218) Ezetimibe (n=73) Evolocumab (n=145) Age (years) Male Gender 50% 47% 54% Coronary Heart Disease 35% 29% 33% NCEP-ATP III High Risk 63% 52% 58% I to era ceto 3 stati s 82% 82% 82% Total Cholesterol (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl)

34 Phase A: Study Drug Discontinuation Events Intolerable Muscle Symptoms N = 491 On atorvastatin, but not placebo 209 (42.6%)* On placebo, but not atorvastatin 130 (26.5%) On both placebo and atorvastatin 48 (9.8%) No symptoms on either treatment 85 (17.3%) Did not complete Phase A 20/511 Bypassed Phase A duetock e evatio 10xULN 19 (3.9%)* *218 of these 228 eligible patients proceeded to Phase B

35 Phase B: Key Primary and Secondary Outcomes Ezetimibe (n=73) Evolocumab (n=145) P value Co-Primary Primary Endpoints LDL-C (week 24) -16.7% -52.8% <.001 LDL-C (mean weeks 22 and 24) -16.7% -54.5% <.001 Selected Secondary Endpoints (Week 24) Lipoprotein (a) +0.2% -21.1% <.001 HDL-C +2.9% +7.4%.008 Triglycerides -1.1% -2.9% NS Other secondary endpoints: Changes in total cholesterol, non-hdl-c, Apo B, total cholesterol/hdl-c ratio, Apo B/Apo A1 ratio, significant (P<.001)

36 LDL-C Values Over Time During Phase B 0 Percent Change in LDL-C (%) Mean reduction 16.7% (LDL-C = 181 mg/dl) Mean reduction 53.0% (LDL-C = 104 mg/dl) Weeks Following Randomization in Phase B Ezetimibe Evolocumab

37 CONCLUSIONES 42.6 % Historia de intolerancia a las estatinas. Presentan síntomas con Atorvastatina 20 mg y NO en placebo. 26.5% presentaron síntomas musculares con placebo. No Atorvastatina. Evolucumab comparado con ezetimibe reduce significativamente el LDL y otras partículas aterogenicas. Ezetimibe / Evolucumab escasamente producen síntomas musculares ( Ezetimibe 6 % Evolucumab 0.7 % )

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40 The ACCELERATE Trial Impact of the Cholesteryl Ester Transfer Protein Inhibitor Evacetrapib on Cardiovascular Outcome Stephen J Nicholls for the ACCELERATE investigators Disclosure Research support: AstraZeneca, Amgen, Anthera, Eli Lilly, Novartis, Cerenis The Medicines Company, Resverlogix, InfraReDx, Roche and LipoScience Consulting and honoraria: AstraZeneca, Eli Lilly, Anthera, Merck, Takeda, Resverlogix, Sanofi-Aventis, CSL Behring, Esperion, Boehringer Ingelheim ACCELERATE was sponsored by Eli Lilly and Company

41 Role of Cholesteryl Ester Transfer Protein (CETP) Liver VLDL FC CE CE TG TG CE LPL FFA Adipose and other tissues LDL SR-BI CETP CETP TG CE LDL receptor Liver LDL receptor HDL TG CE LCAT CE FC Cell in peripheral tissue

42 ACCELERATE Trial Design 12,092 patients at high vascular risk, defined as: ACS within days Diabetes with coronary disease Peripheral arterial disease Cerebrovascular disease 1:1 randomization Evacetrapib 130 mg Placebo Event driven - Primary endpoint in 1670 patients (CV death, MI, stroke, coronary revascularization or hosp. for unstable angina) Minimum of 700 patients with hard events (CV death, MI or stroke), minimum of 1.5 years of follow-up per patient 84% power to detect a 13.5% reduction in the primary endpoint

43 Early Termination of Trial On October 12, 2015 study terminated prematurely on the recommendation of the Data Monitoring Committee for clinical futility for the primary composite endpoint. These findings represent the preliminary analyses after 98.8% of patients completed their end of study visit, prior to final database lock.

44 Baseline Clinical Characteristics Parameter Placebo (n=6054) Evacetrapib (n=6038) Age (years) Males 77% 77% Caucasian 83% 82% Mean body mass index History of hypertension 88% 87% History of diabetes 68% 68% Current smoker 16% 17% Prior myocardial infarction 67% 67% Prior PCI 72% 71% Prior CABG 29% 30%

45 Preliminary analysis prior to formal database lock Percent Change in HDL-C Levels During the Trial 175 Percent Change in HDL-C (%) Mean HDL-C = 104 mg/dl Mean difference = 130% Mean HDL-C = 46 mg/dl Evacetrapib Placebo Months Following Randomization

46 Percent Change in LDL-C Levels During the Trial 20 Percent Change in LDL-C (%) Mean LDL-C = 84 mg/dl Mean difference 37% Mean LDL-C = 55 mg/dl Evacetrapib Placebo Months Following Randomization Preliminary analysis prior to formal database lock

47 Cumulative Incidence of Primary Efficacy Endpoint Cumulative Event Rate (%) Evacetrapib, 774 events (12.8%) Placebo, 768 events (12.7%) HR = % CI, P=0.85 Months Following Randomization Preliminary analysis prior to formal database lock

48 Secondary Efficacy Endpoints Placebo (n=6054) Evacetrapib (n=6038) CV death, MI, stroke 444 (7.3) 434 (7.2) CV death 163 (2.7) 140 (2.3) MI 255 (4.2) 256 (4.2) Stroke 95 (1.6) 92 (1.5) Hospitalization for unstable angina 143 (2.4) 155 (2.6) Coronary revascularization 482 (8.0%) 485 (8.0%) All cause mortality 269 (4.1) 227 (3.8) HR (95% CI) 0.98 (0.86,1.12) 0.86 (0.68,1.08) 1.00 (0.84,1.19) 0.97 (0.73,1.29) 1.08 (0.86,1.36) 1.01 (0.89, 1.14) 0.84 ( ) P Value Preliminary analysis prior to formal database lock

49 Systolic Blood Pressure During the Trial 134 Mean difference = 0.9 mm Hg (P <0.001) 133 Mean Systolic BP = 132 mm Hg Systolic BP (mm Hg) Mean Systolic BP = 131 mm Hg Evacetrapib Placebo Months Following Randomization Preliminary analysis prior to formal database lock

50 CONCLUSIONES 37 % Disminución LDL, 130 % Aumento en HDL. Evacetatrip no reduce el desenlace compuesto de eventos cardiovasculares. Los hallazgos dan información importante. En espera de los resultados del estudio REVEAL. Anacetatrip.

51 MENSAJE Reducción 28 % del riesgo Cardiovascular en prevención primaria. Alternativas en pacientes con intolerancia a estatinas = LIPID PATHWAY. Estudios con posible impacto C.V. ( inhibidores CTEP )

52 GRACIAS