Cholesterol verlaging (om cardiovasculair risico te verlagen) Toen, - - PowerPoint PPT Presentation
Cholesterol verlaging (om cardiovasculair risico te verlagen) Toen, nu en straks Erik Stroes AMC, The Netherlands Outline Cholesterol verlaging: toen, nu en straks Cholesterol verlaging toen Fire and Forget Statins only
Erik Stroes AMC, The Netherlands
– Fire and Forget – Statins only
Boren J, Williams KJ. Curr Opin Lipidol 2016;27:473–83
Boren, Cur Op Lip 2016
ACC=American College of Cardiologists; AHA=American Heart Association; ASCVD= atherosclerotic cardiovascular disease; ESRD=end-stage renal disease; LDL-C=low-density lipoprotein cholesterol; RCT=randomized controlled trials.
2013 ACC/AHA guidelines state that reduction of CVD events according to risk should be achieved with statin treatment in 4 groups with increased CV risk
Clinical ASCVD Diabetes mellitus (type 1 or 2) and age of 40–75 yr and LDL-C 70–189 mg/dL High-intensity statin therapy If risk <7.5%*, moderate- intensity statin therapy If risk ≥7.5%*, high-intensity statin therapy No diabetes mellitus and age
LDL-C 70–189 mg/dL Calculate 10-year risk* of ASCVD If risk ≥7.5, moderate-to-high- intensity statin therapy LDL-C ≥190 mg/dL High-intensity statin therapy Calculate 10-year risk* of ASCVD Patients >21 yr of age without heart failure or ESRD Screen for ASCVD risk factors Measure LDL-C
Goff et al, JACC 2013 ePub Nov 12.; Stone et al. JACC 2014; 63:2889-934; Keaney et al. NEJM 2013; ePub Nov 27.
ACC=American College of Cardiologists; AHA=American Heart Association; ASCVD= atherosclerotic cardiovascular disease; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; RCT=randomized controlled trials. Stone et al. JACC 2014; 63:2889-934; Keaney et al. NEJM 2013; ePub Nov 27
since no RCTs have been done to specifically treat to goals, an optimal goal is not supported
treat high-risk patients who:
– Fire and Forget – Statins only
– Van LDL-c target naar LDL-c eradicatie – Van statines naar combinatie therapie
– Low-frequency injectables – Tailored therapy
Ference BA, et al. J Am Coll Cardiol 2015;65:1552–61.
Lower LDL-C (mg/dL)
Proportional reduction in CHD risk (log scale) 30% 20% 10%
1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0 21.0
GISSI- P A to Z SEARCH ALLHAT-LLT
Genetically lower LDL-C Pharmacologically lower LDL-C
IMPROVE-IT
Combined NPC1L1 & HMGCR LDL-C score HMGCR LDL-C score NPC1L1 LDL-C score
~20% reduction in CHD risk for each 1mmol/L (38.6mg/dL) lower LDL-C 69.5% reduction in CHD risk for each 1mmol/L (38.6mg/dL) lower LDL-C
NPC1L1 LDL-C score HMGCR LDL-C score LDLR rs2228671 LDLR rs6511720 PCSK9 46L rs11206510 ABCG5/8 rs4299376 HMGCR rs12916 NPC1L1 rs217386
2 x 2 Factorial Mendelian Randomisation Study
Less ‘LDL-exposure’ years leads to prevention of disease formation
Wiegman et al. European Heart Journal doi:10.1093/eurheartj/ehv157
hypercholesterolaemia showing the potential impact of early recognition and treatment on evolution of the condition
Ezetimibe induced LDL-c lowering reduces CV-risk
Cannon et al. N Engl J Med 2015;372:2387–2397.
50% 40% 30% 20% 10% 0% 0.5 1.0 1.5 2.0
Reduction in LDL-C (mmol/L) Proportional Reduction in Event Rate (SE)
IMPROVE-IT CTT-meta-analysis
10
Evolocumab SC
140 mg Q2W or 420 mg QM
Placebo SC
Q2W or QM LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL
Follow-up Q 12 weeks
Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD)
RANDOMIZED DOUBLE BLIND
Sabatine MS et al. Am Heart J 2016;173:94-101
0,0 0,5 1,0 1,5 2,0 2,5 4 12 24 48 72 96 120 144 168 LDL-C (mM) Weeks after randomization
Evolocumab Median 0.78 mM IQR [0.49-1.27] Placebo 59% mean decline P<0.00001
Absolute↓1.45 mM (1.42-1.47)
14,6 9,9 12,6 7,9
5 10 15
CV death, MI, stroke, UA, cor revasc CV death, MI, stroke
KM Rate (%) at 3 Years Placebo Evolocumab HR 0.80 (0.73-0.88) P<0.00001 HR 0.85 (0.79-0.92) P<0.0001 Sabatine MS et al. New Engl J Med 2017;376:1713-22
Independent from ‘pathway’
12
CTTC data from Lancet 2010;376:1670-81 Hazard Ratio (95% CI) per 1 mmol/L reduction in LDL-C
Median follow-up
4.9 years on average in CTTC meta-analysis
Supplement to Sabatine, et al. N Engl J Med 2017; March 17: online
MG Silverman et al - JAMA. 2016;316(12):1289 1297. Weighted Between-Group Difference in Achieved Low-Density Lipoprotein Cholesterol (LDL-C) Level and Relative Risk for Major Vascular Events for Each Class of Intervention The RR for major vascular events per 1- mmol/L reduction in LDL-C was:
statins
established non-statin interventions that work primarily via up-regulation
bile acid sequestrants, ileal bypass, and ezetimibe)
.25).
The use of statin and non-statin therapies that act via up-regulation of LDL receptor expression to reduce LDL-C were associated with similar RRs of major vascular events per change in LDL-C.
to what occurs when CETP & HMGCR inhibition are combined
Odds Ratio
Ference, JAMA 2017 aug.
Achieved on-trial LDL-C concentration, mg/dL (mmol/L) < 50 (< 1.29) (n = 4375) 50–< 75 (1.29–< 1.94) (n = 10,395) 75–< 100 (1.94–< 2.58) (n = 10,091) 100–< 125 (2.58–< 3.23) (n = 8953) 125–< 150 3.23– <3.88 (n = 3128) 150–< 175 (3.88–< 4.52) (n = 836) ≥ 175 (≥ 4.52) (n = 375) Major CV events Unadjusted HR (95% CI) Adjusted HR (95% CI)* 194 (4.4) 0.20 (0.16–0.25)
0.44
(0.35–0.55) 1185 (11.4) 0.40 (0.33–0.48)
0.51
(0.42–0.62) 1664 (16.5) 0.50 (0.42–0.60)
0.56
(0.46–0.67) 1480 (16.5) 0.48 (0.40–0.58)
0.58
(0.48–0.69) 557 (17.8) 0.51 (0.42–0.62)
0.64
(0.53–0.79) 184 (22.0) 0.64 (0.51–0.81)
0.71
(0.56–0.89) 123 (32.8) 1.00 (ref)
1.00
(ref) Major coronary events Unadjusted HR (95% CI) Adjusted HR (95% CI)* 129 (2.9) 0.15 (0.12–0.20) 0.47 (0.36–0.61) 918 (8.8) 0.36 (0.29–0.43) 0.53 (0.43–0.65) 1431 (14.2) 0.50 (0.41–0.61) 0.58 (0.48–0.71) 1336 (14.9) 0.51 (0.42–0.62) 0.62 (0.51–0.75) 492 (15.7) 0.53 (0.43–0.65) 0.67 (0.55–0.83) 170 (20.3) 0.69 (0.54–0.88) 0.78 (0.61–0.99) 107 (28.5) 1.00 (ref) 1.00 (ref) Major cerebrovascular events Unadjusted HR (95% CI) Adjusted HR (95% CI)* 72 (1.6) 0.47 (0.29–0.74) 0.36 (0.22–0.59) 315 (3.0) 0.62 (0.41–0.95) 0.46 (0.30–0.71) 302 (3.0) 0.52 (0.34–0.79) 0.49 (0.32–0.75) 205 (2.3) 0.38 (0.25–0.58) 0.45 (0.29–0.69) 91 (2.9) 0.47 (0.30–0.75) 0.58 (0.36–0.91) 21 (2.5) 0.41 (0.23–0.74) 0.43 (0.24–0.78) 23 (6.1) 1.00 (ref) 1.00 (ref) Data taken from 8 randomized statin trials. Values are n (%) unless otherwise indicated. The highest LDL-C category was used as the reference category. *Adjusted for sex, age, smoking status, presence of diabetes mellitus, systolic blood pressure, HDL-C concentration and trial. HDL-C, high-density lipoprotein cholesterol;
Boekholdt SM, et al. J Am Coll Cardiol 2014;64:485–94.
beyond any ‘target’ defined in guidelines
Achieved LDL-C in mM at 4 Weeks
At Randomization
<0.5 (N=2669) 0.5-1.3 (N=8003) 1.3-1.8 (N=3444) 1.8-2.6 (N=7471) >2.6 (N=4395)
Median Lipid values LDL-C, mM 2.1 2.4 2.2 2.3 3.0 Total cholesterol, mM 4.0 4.3 4.2 4.2 5.0 Triglycerides, mM 1.5 1.5 1.6 1.4 1.6 HDL-C, mM 1.1 1.1 1.1 1.1 1.2 Lipoprotein (a), nM 22 43 32 37 48 High potency statin, % (> Atorvastatin 40 mg/d) 63 69 70 70 72 Ezetimibe, % 4.1 5.0 5.4 4.6 7.4
Giugliano RP, Lancet 2017
CV Death, MI, or Stroke
Giugliano RP, Lancet 2017
LDL-C (mM) Adj HR (95% CI) <0.5 0.69 (0.56-0.85) 0.5-1.3 0.75 (0.64-0.86) 1.3-1.8 0.87 (0.73-1.04) 1.8-2.6 0.90 (0.78-1.04) > 2.6 referent
P = 0.0001
LDL-C (mM) at 4 weeks
11,9 7,8 7,3 4,4
5 10 15
CVD, MI, Stroke, UA, Cor Revasc CVD, MI, Stroke
≥2.6 mM <0.26 mM Cardiovascular Efficacy
HR 0.69 (0.49-0.97) P=0.03 HR 0.59 (0.37-0.92) P=0.02
N=504: Median [IQR] LDL-C 0.18 [0.13-0.23] mM = 7 [5-9] mg/dL
23,3 3,4 22,8 3,4
5 10 15 20 25 30
Serious adverse event AE -> drug discontinued
≥2.6 mM <0.26 mM
HR 0.94 (0.74-1.20) P=0.61 HR 1.08 (0.63-1.85) P=0.78
Safety
Giugliano RP, Lancet 2017
Determined by absolute CV-risk and [LDL-c]
Robinson JG et al. JACC. 2016.
>30% 10-year ASCVD risk Clinical ASCVD + diabetes Clinical ASCVD + chronic kidney disease Recent acute coronary syndrome (<3 months) Clinical ASCVD with multiple recurrent events* Percent LDL-C reduction Add ezetimibe Combination therapy¥ PCK9 mAb PCSK9 mAb maximum dose Initial LDL-C 20% 35% 50% 65% 190 mg/dl 32 18 13 10 160 mg/dl 38 22 15 12 130 mg/dl 47 27 19 15 100 mg/dl 61 35 25 19 70 mg/dl 88 50 35 27
Possible NNTs with PCKS9i for the recommended populations from the ESC/EAS consensus statement
(PCSK9i recommended by the ESC/EAS for rapid progression of ASCVD and LDL-C>100 mg/dl
– Fire and Forget – Statins only
– Van LDL-c target naar LDL-c eradicatie – Van statines naar combinatie therapie,
– Improving adherance
– Lp(a) – Remnant cholesterol
– Cantos / COMPASS / FOURIER
Meta-analysis of 44 studies, n= 1 978 919; 135 627 CVD events; 94 126 cases of all-cause mortality
9% of all CVD events in Europe could be attributed to poor adherence to vascular medications alone
Chowdhury et al., EHJ 2013;34:2940–8
RNAi is an intrinsic process for inhibiting mRNA
dsRNA dicer
Cleavage
Natural process of RNA interference Synthetic siRNA
mRNA
mRNA degradation
Strand separation Complementary pairing Cleavage
Targeted gene silencing
RISC
Single dose results in > 3 months 50% LDL-c lowering
20 30 60 90 120 150 180 210 240 270
Mean percent change (±95% CI)
Days from first injection Placebo 200 mg 300 mg 500 mg
End of study if LDL-C back to baseline
P-value for all comparisons to placebo <0.0001
Ray KK, N Engl J Med 2017
Future: twice a year injection = whole year >50 LDLc reduction
20 30 60 90 120 150 180 210 240 270
Mean percent change (±95% CI)
Days from first injection Placebo 100 mg 200 mg 300 mg
End of study if LDL-C back to baseline
P-value for all comparisons to placebo <0.0001
Ray KK, N Engl J Med 2017
Tsimikas Curr Opin Endocrinol Diabetes Obes 2016;23:157–164
AIM-HIGH 54, JUPITER 62 and LIPID 112 mg/dL
50-73.7 mg/dL
Q4
Prakash TP, Nucleic Acids Res 2014
Viney, Stroes, Tsimikas S, Lancet 2016
Injection site reactions: >80 %
Weekly dose ED50 of 3.9 mg (0.05 mL)
*** *** *** *** *** *** *** *** ***
* * * Viney, Stroes, Tsimikas, Lancet 2016
Injection site reactions: 0 %
Varbo JACC 2013
Apo-CIII antisense potently reduces TG levels and remant chol.
Gaudet et al. NEJM 2015
– Improving adherance
– Lp(a)
– Remnant cholesterol
– CANTOS / COMPASS / FOURIER
Stable CAD (post MI) On Statin, ACE/ARB, BB, ASA Persistent Elevation
Randomized Canakinumab 150 mg SC q 3 months Randomized Placebo SC q 3 months
Primary CV Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE)
Randomized Canakinumab 300 mg SC q 3 months*
Key Secondary CV Endpoint: MACE + Unstable Angina Requiring Unplanned Revascularization (MACE+)
Randomized Canakinumab 50 mg SC q 3 months
Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)
N = 10,061 39 Countries April 2011 - June 2017 1490 Primary Events
Ridker N Engl J Med 2017
Critical Non-Cardiovascular Safety Endpoints: Cancer and Cancer Mortality, Infection and Infection Mortality
1 2 3 4 5 Follow-up Years 0.00 0.05 0.10 0.15 0.20 0.25 Cumulative Incidence
MACE
Placebo 150/300mg
Placebo SC q 3 months Canakinumab 150/300 SC q 3 months
HR 0.85 95%CI 0.76-0.96 P = 0.007
39% reduction in hsCRP No change in LDLC 15% reduction in MACE Cumulative Incidence (%)
Ridker PM et al, NEJM 2017
Differential benefits: > median CRP reduction ? HR 0.73
Canakinumab SC q 3 months
Adverse Event Placebo
(N=3347)
50 mg
(N=2170)
150 mg
(N=2284)
300 mg
(N=2263)
P-trend Any SAE
12.0 11.4 11.7 12.3 0.43
Leukopenia
0.24 0.30 0.37 0.52 0.002
Any infection
2.86 3.03 3.13 3.25
0.12 Fatal infection
0.18 0.31 0.28 0.34
0.09/0.02* Injection site reaction
0.23 0.27 0.28 0.30 0.49
Any Malignancy
1.88 1.85 1.69 1.72 0.31
Fatal Malignancy
0.64 0.55 0.50 0.31 0.0007
Arthritis
3.32 2.15 2.17 2.47 0.002
Osteoarthritis
1.67 1.21 1.12 1.30 0.04
Gout
0.80 0.43 0.35 0.37 0.0001
ALT > 3x normal
1.4 1.9 1.9 2.0 0.19
CANTOS: Additional Outcomes (per 100 person years of exposure)
Ridker N Enlg J Med 2017
Eikelboom J, N Engl J Med 2017
Eikelboom J, N Engl J Med 2017
Landrey M, N Engl J Med 2017
Landrey M, N Engl J Med 2017
Landrey M, N Engl J Med 2017; Ference B, JAMA 2017.
Further lipid modulation Ezetimibe 6% RRR PCSK9-ab: (15-) 30% RRR CETPi: 9% RRR LDL 130 mg/dL (3.3 mmol/L) CRP 1.8 mg/L
“Residual Lipid Risk”
High CV-risk High Intensity Statin Inflammation Reduction IL1B-ab: (15-) 27% RRR LDL 70 mg/dL (1.8 mmol/L) CRP 3.8 mg/L
“Residual Inflamm Risk” “Residual Thromb. Risk”
LDL 92 mg/dL (2.4 mmol/L) CRP 1.9 mg/L Coagulation Reduction Rivaroxa: 24% RRR
Application of a readily applicable ‘marker of benefit/harm’: Prior to initiating personalized therapy
Nahrendorf, Stroes, et al J Am Coll Cardiol 2015;65(15)1583-91.
Multimodal imaging:
Ganz, P. et al. .JAMA 2016;315:2532-41
– Improving adherance
– Lp(a)
– Remnant cholesterol
– CANTOS / COMPASS / FOURIER ♬
– John Kastelein – Bert Groen – Kees Hovingh – Max Nieuwdorp
– Alberico Catapano – Wolfgang Koenig – Borge Nordestgaard
Funding: HORIZON2020 REPROGRAM; CVON-GENIUS; FP7-Nano-Athero; FP7-TRANSCARD
– Matthias Nahrendorf – Sam Tsimikas – Zahi Fayad
– Renate Hoogeveen – Lotte Stiekema – Rens Reeskamp – Rutger Verbeek – Fleur vd Valk – Simone Verweij