MS Sabatine, RP Giugliano, AC Keech, PS Sever, SA Murphy and TR Pedersen, for the FOURIER Steering Committee & Investigators

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1 Evolocumab Reduces Cardiovascular Events in Patients with Baseline LDL-C <70 mg/dl and in Patients Already on Maximum Intensity Statin: An Analysis from FOURIER MS Sabatine, RP Giugliano, AC Keech, PS Sever, SA Murphy and TR Pedersen, for the FOURIER Steering Committee & Investigators National Lipid Association Scientific Sessions Late-Breaking Clinical Trial May 20, 2017

2 Disclosures Research Grant Support through BWH: Amgen; AstraZeneca; Daiichi-Sankyo; Eisai; GlaxoSmithKline; Intarcia; Janssen Research Development; MedImmune; Merck; Novartis; Pfizer; Poxel; Takeda Scientific Advisory Boards & Consulting: Amgen; CVS Caremark; Esperion; Intarcia; Ionis; MedImmune; Merck; Novartis

3 Trial Design 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD) Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) LDL-C 70 mg/dl or non-hdl-c 100 mg/dl Evolocumab SC 140 mg Q2W or 420 mg QM RANDOMIZED DOUBLE BLIND Placebo SC Q2W or QM Follow-up Q 12 weeks Sabatine MS et al. Am Heart J 2016;173:94-101

4 Primary & Key Secondary Endpoints 16% 16% CV Death, MI, Stroke, Hosp for UA, or Cor Revasc 14% 12% 10% 8% 6% 4% 2% Hazard ratio 0.85 (95% CI, ) P< Placebo Evolocumab CV Death, MI, or Stroke 14% 12% 10% 8% 6% 4% 2% Hazard ratio 0.80 (95% CI, ) P< Placebo Evolocumab 0% % Months from Randomization Sabatine MS et al. NEJM 2017;376:

5 Current Guidelines: LDL-C Targets J Clin Lipidol 2015;9:129-69; EHJ 2016;37: ; JACC 2016;68:92-105

6 Current Guidelines: Statin Intensity J Clin Lipidol 2015;9:129-69; EHJ 2016;37: ; Circ 2013;129:S1-45

7 Hypothesis Even patients starting with an LDL-C below current targets or already on maximum intensity statin therapy will derive additional cardiovascular risk reduction from further lipid lowering with evolocumab.

8 Objectives To evaluate efficacy and safety of evolocumab in two key subgroups: Patients with baseline LDL-C <70 mg/dl* Patients on maximum intensity statin therapy, defined as atorvastatin 80 mg/d or rosuvastatin 40 mg/d *Could have had final screening lipids prior to day of randomization that demonstrated either non-hdl-c 100 mg/dl or LDL-C 70 mg/dl. LDL-C was calculated using Friedewald equation, except if <40 mg/dl or if TG >400 mg/dl, in which case LDL-C was measured by preparative ultracentrifugation.

9 Baseline LDL-C N=2034 Number of Subjects < ) 55-60) 60-65) 65-70) 70-75) 75-80) 80-85) 85-90) 90-95) ) ) ) ) ) ) ) ) ) ) ) ) ) >=160 LDL-C (mg/dl)

10 Baseline Characteristics Characteristic LDL-C <70 mg/dl LDL-C 70 mg/dl Number ,529 Age, years, mean (SD) 62 (9) 63 (9) Male sex (%) Type of cardiovascular disease (%) Myocardial infarction Stroke (non-hemorrhagic) Symptomatic PAD Diabetes (%) Pooled data; no differences between treatment arms

11 Baseline Characteristics Characteristic LDL-C <70 mg/dl LDL-C 70 mg/dl Maximum intensity statin (%) High but not max intensity statin (%) Ezetimibe (%) 4 5 LDL-C, mg/dl, median (IQR) 65.5 (61-68) 93.5 ( ) Non-HDL-C, mg/dl, median (IQR) 100 (89-111) 123 ( ) Maximum intensity statin: atorvastatin 80 mg/d or rosuvastatin 40 mg/d High but not max intensity statin: atorvastatin 40 to <80 mg/d, rosuvastatin 20 to <40 mg/d, or simvastatin 80 mg/d Pooled data; no differences between treatment arms

12 LDL Cholesterol In patients with baseline LDL-C<70 mg/dl 100 LDL Cholesterol (mg/dl) Placebo (median 66 mg/dl, IQR mg/dl) 66% mean reduction (95%CI 62-69), P< Weeks Evolocumab (median 21 mg/dl, IQR mg/dl)

13 Clinical Outcomes by Baseline LDL-C CVD, MI, stroke, UA, or cor revasc HR (95% CI) P interaction All Patients 0.85 ( ) Baseline LDL-C <70 mg/dl 0.80 ( ) Baseline LDL-C 70 mg/dl 0.86 ( ) 0.65 CVD, MI, or stroke All Patients 0.80 ( ) Baseline LDL-C <70 mg/dl 0.70 ( ) Baseline LDL-C 70 mg/dl 0.81 ( ) EvoMab better Pbo better

14 Patients with Baseline LDL-C <70 mg/dl 9% CV Death, MI, Stroke 8% 7% 6% 5% 4% 3% N=2034 Hazard ratio 0.70 (95% CI, ) Placebo Evolocumab 7.7% 5.2% 2% 1% 0% Months from Randomization

15 Safety In patients with baseline LDL-C<70 mg/dl Evolocumab (N=1030) Placebo (N=1003) Adverse events (%) Any Serious Allergic reaction Injection-site reaction Treatment-related and led to d/c of study drug Muscle-related Cataract Diabetes (new-onset) Neurocognitive Laboratory results (%) ALT or AST >3 ULN CK >5 ULN New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC. No significant interactions between baseline LDL-C, evolocumab, and the rates of adverse events.

16 Baseline Statin Intensity Maximum High but not maximum Moderate 42 Low/unknown Maximum intensity statin: atorvastatin 80 mg/d or rosuvastatin 40 mg/d High but not max intensity statin: atorvastatin 40 to <80 mg/d, rosuvastatin 20 to <40 mg/d, or simvastatin 80 mg/d

17 Baseline Characteristics Characteristic Maximum Intensity Statin Non-Maximum Intensity Statin Number ,031 Age, years, mean (SD) 61 (9) 63 (9) Male sex (%) Type of cardiovascular disease (%) Myocardial infarction Stroke (non-hemorrhagic) Symptomatic PAD Diabetes (%) Pooled data; no differences between treatment arms

18 Baseline Characteristics Characteristic Maximum Intensity Statin Non-Maximum Intensity Statin Maximum intensity statin (%) High but not max intensity statin (%) 0 58 Ezetimibe (%) 9 4 LDL-C, mg/dl, median (IQR) 93 (80-112) 91 (80-108) Non-HDL-C, mg/dl, median (IQR) 122 ( ) 121 ( ) Maximum intensity statin: atorvastatin 80 mg/d or rosuvastatin 40 mg/d High but not max intensity statin: atorvastatin 40 to <80 mg/d, rosuvastatin 20 to <40 mg/d, or simvastatin 80 mg/d Pooled data; no differences between treatment arms

19 LDL Cholesterol In patients on maximum intensity statin Placebo (median 91 mg/dl, IQR mg/dl) LDL Cholesterol (mg/dl) % mean reduction (95%CI 57-59), P< Evolocumab (median 32 mg/dl, IQR mg/dl) Weeks

20 Clinical Outcomes by Statin Intensity CVD, MI, stroke, UA, or cor revasc HR (95% CI) P interaction All Patients 0.85 ( ) Maximum intensity statin 0.86 ( ) Lesser intensity statin 0.85 ( ) 0.88 CVD, MI, or stroke All Patients 0.80 ( ) Maximum intensity statin 0.78 ( ) Lesser intensity statin 0.81 ( ) EvoMab better Pbo better

21 10% 9% Patients on Maximum Intensity Statin N= % CV Death, MI, Stroke 8% 7% 6% 5% 4% 3% Hazard ratio 0.78 (95% CI, ) Placebo Evolocumab 6.8% 2% 1% 0% Months from Randomization

22 Safety In patients on maximum intensity statin Evolocumab (N=3754) Placebo (N=3770) Adverse events (%) Any Serious Allergic reaction Injection-site reaction Treatment-related and led to d/c of study drug Muscle-related Cataract Diabetes (new-onset) Neurocognitive Laboratory results (%) ALT or AST >3 ULN CK >5 ULN New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC. No significant interactions between statin intensity, evolocumab, and the rates of adverse events.

23 Conclusions Evolocumab safely CV events in patients w/ stable ASCVD to a similar degree whether the baseline LDL-C was <70 or 70 mg/dl, and regardless of whether the background statin was maximal intensity or not. These findings support using evolocumab to go beyond what is recommended in current guidelines to lower CV risk in well-treated patients. slides available at