Ponencia presentada por el Dr. Juan José Gómez Doblas en el directo online ‘Fármacos que mejoran el pronóstico cardiovascular’, realizado en la Casa del Corazón el 5 de junio de 2018

1. Inhibidores PCSK9
Dr. JJ Gómez Doblas
Área del Corazón
Hospital Universitario Virgen de la Victoria
Málaga

2. Indice
• Penetrancia de IPCSK9 en vida real en España
• Beneficios en la práctica clínica diaria de nuestros
pacientes más allá de la supervivencia
• Reducción de mortalidad reducción de eventos de
IPCSK9
• Dificultades para iniciar IPCSK9
• Y el futuro…

3. Lambert G et al. J Lipid Res. 2012;53:2515-2524
MONOCLONALES ANTI-PCSK9

4. Evolocumab
– Fully human anti-
PCSK9 mAb
– ~60%  LDL-C
– Safe & well-tolerated in
Ph 2 & 3 studies
– Exploratory data
suggested  CV events
Sever P & Mackay J. Br J Cardiol 2014;21:91-3
Giugliano RP, et al. Lancet 2012;380:2007-17
Sabatine MS, et al. NEJM 2015;372:1500-9
Background
Proprotein convertase subtilisin/kexin type 9 (PCSK9)
– Chaperones LDL-R to destruction   circulating LDL-C
– Loss-of-fxn genetic variants   LDL-R   LDL-C &  risk of MI
evolocumab
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School

9. Estudio RiCARD2
Evaluación del control glucémico en
pacientes con alto riesgo cardiovascular y
diabetes mellitus tipo 2 en consultas de
atención primaria y cardiología

10. 2. Hipolipemiante
87,20%
12,10%
6,60%
1,10%
78,30%
5,00%
4,20%
0,80%
83,04%
8,77%
5,46%
0,97%
Estatinas
p=0,009
Ezetimibe
p=0,005
Fibratos
p=0,248
Otros Hipolipemiantes
p=1
Cardiología Primaria Total
Tratamientos

11. Control lípidos
Cardiología Primaria
N total P valor
n % n %
Control cLDL
<70 117 43,0% 45 18,8% 162
<0,001
≥70 155 57 % 195 81,2% 350

12. Estudios de eventos CV en
IPCSK9. Fourier y Odyssey
Outcome
Am Heart J 2014;168:682-689.e1Am Heart J. 2016 Mar;173:94-101.

13. Evolocumab Outcomes Trial:
Study Design Overview
Screening
• Age 40–85 years
• MI, stroke, or PAD
• Additional risk factors (one major or two
minor)
• Optimal background lipid therapy
(including effective dose of statin ±
ezetimibe)
• LDL-C ≥ 70 mg/dL or
non–HDL-C ≥ 100 mg/dL
Evolocumab SC
140 mg Q2W or 420 mg QM
(per subject preference)
n ~ 13,750
Placebo SC
Q2W or QM
(per subject preference)
n ~ 13,750
Randomization1:1
EndofStudy(EOS)
Maximum approximately 15 weeks D1 W4 W12 W24 Q24W Number of
key 20
endpoints
achieved

14. ACC.18
6
Main Inclusion Criteria
• Age ≥40 years
• ACS
• 1 to 12 months prior to randomization
• Acute myocardial infarction (MI) or unstable angina
• High-intensity statin therapy*
• Atorvastatin 40 to 80 mg daily or
• Rosuvastatin 20 to 40 mg daily or
• Maximum tolerated dose of one of these agents for ≥2 weeks
• Inadequate control of lipids
• LDL-C≥70 mg/dL (1.8 mmol/L) or
• Non-HDL-C≥100 mg/dL (2.6 mmol/L) or
• Apolipoprotein B≥80 mg/dL
*Patients not on statins were authorized to participate if tolerability issues were present and documented
Schwartz GG, et al. Am Heart J 2014;168:682-689.e1.

15. An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Endpoints
• Efficacy
– Primary: CV death, MI, stroke, hosp. for UA, or coronary revasc
– Key secondary: CV death, MI or stroke
• Safety
– AEs/SAEs
– Events of interest incl. muscle-related, new-onset diabetes,
neurocognitive
– Development of anti-evolocumab Ab (binding and neutralizing)
• TIMI Clinical Events Committee (CEC)
– Adjudicated all efficacy endpoints & new-onset diabetes
– Members unaware of treatment assignment & lipid levels
Sabatine MS et al. Am Heart J 2016;173:94-101

16. ACC.18
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Primary Efficacy Outcome
Time of first occurrence of:
• Coronary heart disease (CHD) death, or
• Non-fatal MI, or
• Fatal or non-fatal ischemic stroke, or
• Unstable angina requiring hospitalization*
All outcomes adjudicated by the Clinical Events Committee, under the auspices of the Duke Clinical Research
Institute (DCRI). Members were unaware of treatment assignment and lipid levels
*Required all of the following:
1. Hospital admission >23 h for MI symptoms,  tempo in prior 48 hours and/or ≥20 min of chest discomfort at rest
2. New ECG findings consistent with ischemia or infarction
3. Angiographically significant obstructive coronary disease
Schwartz GG, et al. Am Heart J 2014;168:682-689.e1.

17. ACC.18
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Major Secondary Efficacy Endpoints
Tested in the following hierarchical sequence:
• CHD event: CHD death, non-fatal MI, unstable angina requiring hospitalization, or
ischemia-driven coronary revascularization*
• Major CHD event: CHD death or non-fatal MI
• CV event: CV death, non-fatal CHD event, or non-fatal ischemic stroke
• All-cause death, non-fatal MI, non-fatal ischemic stroke
• CHD death
• CV death
• All-cause death
*Revascularization performed because of recurrent ACS, new or progressive symptoms of myocardial ischemia or new or
progressive abnormalities on functional testing, except revascularization due to restenosis at a prior coronary intervention site.

18. Acceptablerange
Belowtarget
ACC.18
15
Undesirably high
baseline range
LDL-C (mg/dL)
Target
range
Alirocumab
705015 250
A Target Range for LDL-C
Schwartz GG, et al. Am Heart J 2014;168:682-689.e1.
We attempted to
maximize the number of
patients in the target
range and minimize the
number below target by
blindly titrating
alirocumab (75 or 150
mg SC Q2W) or blindly
switching to placebo.

19. Characteristic Value
Statin use(%)*
High-intensity 69
Moderate-intensity 30
Ezetimibe use(%) 5
Medianlipidmeasures(IQR)–mg/dL
LDL-C 92 (80-109)
Totalcholesterol 168 (151-189)
HDL-C 44 (37-53)
Triglycerides 133 (100-182)
Brigham and Women’s Hospital and Harvard Medical School
Lipid Lowering Therapy
& Lipid Levels at Baseline
Pooled data; no differences between treatment arms
*Per protocol, patients were to be on atorva ≥20 mg/d or equivalent.
1% were on low intensity or intensity data were missing.
Statin intensity defined perACC/AHA2013 Cholesterol Guidelines.
An Academic Research Organization of

20. Therapy,n(%) Alirocumab
(N=9462)
Placebo
(N=9462)
High-dose atorvastatin/rosuvastatin 8380(88.6) 8431(89.1)
Low-/moderate-dose
atorvastatin/rosuvastatin
830(8.8) 777(8.2)
Other statin 19(0.2) 27(0.3)
Ezetimibe, with or withoutstatin 269(2.8) 285(3.0)
No lipid-lowering therapy* 87(0.9) 91(1.0)
ACC.18
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Baseline Lipid-Lowering Therapy
*Patients not on statins were authorized to participate if tolerability issues were present and documented

21. Evolocumab Outcomes Trial:
Resultados
Placebo
Median 92 mg/dL
Evolocumab
Median 30 mg/dL
13,251 13,151 12,954 12,596 12,311 10,812 6,926 3,352 79013,779Placebo
13,288 13,144 12,964 12,645 12,359 10,902 6,958 3,323 76813,784Evolocumab
No. at risk
4
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Weeks
59% mean reduction (95%CI 58-60), P < 0.001
Absolute reduction: 56 mg/dL (95% CI 55-57)
LDLCholesterol(mg/dL)

22. MeanLDL-C(mg/dL)
ACC.18
29
96.4
42.3
15
0
105
90
75
60
45
30
0 4 8 12 16 20 24 28 32 36 40 44 48
93.3
55.7
mg/dL
–62.7%
37.6
54.1
mg/dL
–61.0%
101.4
48.1
mg/dL
–54.7%
53.3
LDL-C: On-Treatment Analysis
Placebo
Alirocumab
Months Since Randomization
Excludes LDL-C values after premature treatment discontinuation or blinded switch to placebo
Approximately 75% of months of active treatment were at the 75 mg dose

23. CVDeath,MI,Stroke,
HospforUA,orCorRevasc
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
10%
8%
6%
4%
2%
0%
14%
12%
16%
Primary Endpoint
Evolocumab
Placebo
Months from Randomization
0 6 12 18 24 30 36
Hazard ratio 0.85
(95% CI, 0.79-0.92)
P<0.0001
14.6%
12.6%

24. CVDeath,MI,orStroke
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
7%
6%
5%
4%
3%
2%
1%
0%
10%
9%
8%
Key Secondary Endpoint
Months from Randomization
0 6 12 18 24 30 36
Hazard ratio 0.80
(95% CI, 0.73-0.88)
P<0.00001
Evolocumab
Placebo
9.9%
7.9%

25. An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Types of CV Outcomes
Endpoint
Evolocumab
(N=13,784)
Placebo
(N=13,780) HR (95% CI)
3-yr Kaplan-Meier rate
CVD, MI, stroke, UA, or revasc
CV death, MI, or stroke
Cardiovascular death
MI
Stroke
Hosp for unstable angina
Coronary revasc
Urgent
Elective
Death from any cause
12.6
7.9
2.5
4.4
2.2
2.2
7.0
3.7
3.9
4.8
14.6
9.9
2.4
6.3
2.6
2.3
9.2
5.4
4.6
4.3
0.85 (0.79-0.92)
0.80 (0.73-0.88)
1.05 (0.88-1.25)
0.73 (0.65-0.82)
0.79 (0.66-0.95)
0.99 (0.82-1.18)
0.78 (0.71-0.86)
0.73 (0.64-0.83)
0.83 (0.73-0.95)
1.04 (0.91-1.19)

26. ACC.18
31
Primary Efficacy Endpoint: MACE
ARR* 1.6%
*Based on cumulative
incidence
MACE: CHD death,
non-fatal MI,
ischemic stroke, or
unstable angina requiring
hospitalization
HR 0.85
(95% CI 0.78, 0.93)
P=0.0003

27. Endpoint,n(%) Alirocumab
(N=9462)
Placebo
(N=9462)
HR(95%CI) Log-rank
P-value
MACE 903(9.5) 1052(11.1) 0.85(0.78,0.93) 0.0003
CHD death 205(2.2) 222(2.3) 0.92(0.76,1.11) 0.38
Non-fatal MI 626(6.6) 722(7.6) 0.86(0.77,0.96) 0.006
Ischemicstroke 111(1.2) 152(1.6) 0.73(0.57,0.93) 0.01
Unstable angina 37(0.4) 60(0.6) 0.61(0.41,0.92) 0.02
ACC.18
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Primary Efficacy and Components

28. Endpoint,n(%) Alirocumab
(N=9462)
Placebo
(N=9462)
HR(95%CI) Log-rank
P-value
CHD event 1199(12.7) 1349(14.3) 0.88(0.81,0.95) 0.001
Major CHD event 793(8.4) 899(9.5) 0.88(0.80,0.96) 0.006
CV event 1301(13.7) 1474(15.6) 0.87(0.81,0.94) 0.0003
Death, MI, ischemic
stroke
973(10.3) 1126(11.9) 0.86(0.79,0.93) 0.0003
CHD death 205(2.2) 222(2.3) 0.92(0.76,1.11) 0.38
CV death 240(2.5) 271(2.9) 0.88(0.74,1.05) 0.15
All-cause death 334(3.5) 392(4.1) 0.85(0.73,0.98) 0.026*
ACC.18
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Main Secondary Efficacy Endpoints:
Hierarchical Testing
*Nominal P-value

29. An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
P<0.0001
Lower LDL-C Is Better
Patients divided by quartile of baseline LDL-C and by treatment arm
Q4
Q3
Q2
Q1
Q4
Q3
Q2
Q1
Placebo
Evolocumab

30. Safety
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 (%)
Binding Ab
Neutralizing Ab
Evolocumab
(N=13,769)
77.4
24.8
3.1
2.1
1.6
5.0
1.7
8.1
1.6
0.3
none
Placebo
(N=13,756)
77.4
24.7
2.9
1.6
1.5
4.8
1.8
7.7
1.5
n/a
n/aNew-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School

31. 0%
10%
20%
30%
40%
50%
60%
No estatina
Dosis baja
Dosis intermedia
Dosis alta
31,0%
8,1%
47,8%
10,5%
8,4%
4,6%
44,2%
42,8%
2006 2014
TRECE (2006) vs. REPAR (2014):
Utilización de estatinas
Cordero A, et al. Rev Esp Cardiol 2016;69:401-07

32. Pacientes de alto riesgo cardiovascular
Anguita Sa ́nchez M, et al. Necesidades no cubiertas con el tratamiento hipolipemiante oral: documento de posicio ́n de la
Sociedad Espan ̃ola de Cardiologı ́a. Rev Esp Cardiol. 2016.

33. A. Zamora et al. / Rev Esp Cardiol. 2017;xx(x):xxx–xxx
J Am Heart Assoc. 2017 Nov; 6(11): e006537.

34. A. Zamora et al. / Rev Esp Cardiol. 2017;xx(x):xxx–xxx

35. Circulation. 2018;137:338-350

36. Circulation. 2018;137:338-350

38. BARRERAS
• Kazi DS et al. Updated cost-effectiveness analysis of
PCSK9 in- hibitors based on the results of the FOURIER
trial. JAMA. 2017;318:748– 750.
• Fonarow GC et al . Cost-effectiveness of evolocumab
therapy for reducing cardiovascular events in patients with
atherosclerotic cardiovascular disease. JAMA Cardiol.
2017;2:1069–1078
• Arrieta A et al Updated cost-effectiveness assessments of
PCSK9 inhibitors from the perspectives of the health system
and private payers: insights derived from the FOURIER
Trial. JAMA Cardiol. 2017;2:1369–1374. doi:

39. @drdoblas
jjgomezdoblas@gmail.com