S1
High-dose or low dose statin, with ezetimibe or without ezetimibe: where do we go from here in secondary prevention?
Colin BaigentMRC Scientist
Professor of EpidemiologyUniversity of Oxford
Colin BaigentProfessor of Epidemiology
Disclosure of potential conflicts of interest
Research contracts: Unrestricted grants to the University of Oxford from Merck, Pfizer and Novartis. I do not accept personal payments from pharmaceutical companies
Consulting: None
Employment in industry: None
Stockholder of a healthcare company: None
Owner of a healthcare company: None
Other: None
Talk outline
• What the trials tell us about the effects of statins on particular CV outcomes?
• What do we know about the effects of ezetimibe in different circumstances?
• Reducing LDL cholesterol in high-risk patients
MRFIT observational study: Relationship between CHD mortality and cholesterol level WITHIN Western range
(Stamler; Diabetes Care 1993)
2.0
1.0
0.5
4.0 5.0 6.0 7.0
Usual total cholesterol (mmol/l)
Rel
ativ
e ri
sk o
f C
HD
dea
th
First CTT cycle: Relation between the proportional
reduction in MAJOR VASCULAR EVENTS and mean
absolute LDL-C reduction at 1 year in 14 statin trials
Lancet 2005; 366: 1267–78
Cholesterol Treatment Trialists(CTT) Collaboration
• Collaborative meta-analysis of individual participant data from randomized trials of LDL-cholesterol (LDL-C) lowering therapy
• Allows detailed analyses of effects of statins:– Efficacy outcomes: Major vascular events (major coronary events,
stroke, or coronary revascularization); vascular mortality
– Safety outcomes: Cancer (site-specific); non-vascular mortality
– Major subgroups: Efficacy and safety in different types of patients (eg, by baseline LDL cholesterol, or by stage of kidney disease)
– By follow-up time (eg, with more prolonged treatment)
• Current cycle:– 21 trials of statin versus control
– 5 trials of more versus less intensive statin
– 24,000 major vascular events among 170,000 participants
CTT Collaboration Lancet 2010
Less statin
Proportional effects on MAJOR VASCULAR EVENTSper mmol/L reduction in LDL cholesterol
0.4 0.6 0.8 1 1.2 1.4
No. of events (% pa)Statin/
More statinControl/ Relative risk (CI)
Statin/morestatin better
Control/lessstatin better
Nonfatal MI
CHD death
Any major coronary event
CABG
PTCA
Unspecified
Any coronary revascularisation
Ischaemic stroke
Haemorrhagic stroke
Unknown stroke
Any stroke
Any major vascular event
3485 (1.0)
1887 (0.5)
5105 (1.4)
1453 (0.4)
1767 (0.5)
2133 (0.6)
5353 (1.5)
1427 (0.4)
257 (0.1)
618 (0.2)
2302 (0.6)
10973 (3.2)
4593 (1.3)
2281 (0.6)
6512 (1.9)
1857 (0.5)
2283 (0.7)
2667 (0.8)
6807 (2.0)
1751 (0.5)
220 (0.1)
709 (0.2)
2680 (0.8)
13350 (4.0)
0.73 (0.69 - 0.78)
0.80 (0.74 - 0.87)
0.76 (0.73 - 0.78)
0.75 (0.69 - 0.82)
0.72 (0.65 - 0.80)
0.76 (0.70 - 0.82)
0.75 (0.72 - 0.78)
0.79 (0.72 - 0.87)
1.12 (0.88 - 1.43)
0.88 (0.76 - 1.01)
0.84 (0.79 - 0.89)
0.78 (0.76 - 0.80)
99% or 95% CI
Proportional effects on CAUSE-SPECIFIC MORTALITY per mmol/L LDL-C reduction
0.5 0.75 1 1.25
Cause of deathStatin/more Control/less
RR (CI) per 1 mmol/L reduction in LDL-C
Control/lessbetter
Statin/morebetter
Vascular causes
Other vascular
Any vascular
Any non-vascular cause
Unknown cause
Any death
404 (0.1)
4220 (1.2)
2943 (0.8)
479 (0.1)
7642 (2.1)
409 (0.1)
4794 (1.3)
2994 (0.8)
539 (0.1)
8327 (2.3)
Events (% p.a.)
0.98 (0.81 - 1.18)
0.86 (0.82 - 0.90)
0.97 (0.92 - 1.03)
0.87 (0.73 - 1.03)
0.90 (0.87 - 0.93)
CHD
Other cardiac
All cardiac
1887 (0.5)
1446 (0.4)
3333 (0.9)
2281 (0.6)
1603 (0.4)
3884 (1.1)
0.80 (0.74 - 0.87)
0.89 (0.81 - 0.98)
0.84 (0.80 - 0.88)
Ischaemic stroke
Haemorrhagic stroke
Unknown stoke
Stroke
153 (0.0)
102 (0.0)
228 (0.1)
483 (0.1)
139 (0.0)
89 (0.0)
273 (0.1)
501 (0.1)
1.04 (0.77 - 1.41)
1.12 (0.77 - 1.62)
0.85 (0.66 - 1.08)
0.96 (0.84 - 1.09)
99% or 95% CI
Study Treatment
comparison
N Target
population
Entry lipid criteria
PROVE-IT A 80 vs. P 40 4162 ACS TC ≤240 mg/dL
A to Z S 40 then S 80
vs. placebo then
S 20
4497 ACS TC ≤250 mg/dL
TNT A 80 vs. A 10 10,001 Prior CHD LDL-C 130-250 mg/dL
TG ≤600 mg/dL
IDEAL A 80 vs. S 20-40 8888 Prior CHD TG ≤600 mg/dL
SEARCH S 80 vs. S 20 12,064 Prior CHD TC ≥4.5 mmol/L or
≥3.5 if on statins
Second CTT cycle: more vs less intensive statin therapy
0%
5%
10%
15%
20%
25%
30%
0.0 0.5 1.0
More vs. Less
(5 trials)
Statin vs. control
(21 trials)
PROVE-IT
TNT
IDEAL
SEARCH
A to Z
CTT meta analysis: Proportional reduction in MAJOR VASCULAR EVENTS versus absolute LDL-C reduction
Pro
po
rtio
na
l re
du
cti
on
in
vascu
lar
even
t ra
te (
95%
CI)
Mean LDL cholesterol difference
between treatment groups (mmol/L)
22% (20%-24%)risk reduction per mmol/L P<0.0001
Lancet 2010
0.4 0.6 0.8 1 1.2 1.4
More statinbetter
Less statinbetter
0.71 (0.58 - 0.87)
0.85 (0.63 - 1.15)
0.74 (0.65 - 0.85)
0.72 (0.55 - 0.95)
0.60 (0.50 - 0.71)
0.78 (0.58 - 1.04)
0.66 (0.60 - 0.73)
0.69 (0.50 - 0.95)
1.39 (0.57 - 3.39)
0.63 (0.24 - 1.66)
0.74 (0.59 - 0.92)
0.72 (0.66 - 0.78)
99% or 95% CI
Nonfatal MI
CHD death
Any major coronary event
CABG
PTCA
Unspecified
Any coronary revascularisation
Ischaemic stroke
Haemorrhagic stroke
Unknown stroke
Any stroke
Any major vascular event
More statin Less statinRelative risk (CI)
More vs less trials: Proportional effects on MAJOR VASCULAR EVENTS per mmol/L reduction in LDL cholesterol
No. of events (% pa)
1175 (1.3)
645 (0.7)
1725 (1.9)
637 (0.7)
1166 (1.3)
447 (0.5)
2250 (2.6)
440 (0.5)
69 (0.1)
63 (0.1)
572 (0.6)
3837 (4.5)
1380 (1.5)
694 (0.7)
1973 (2.2)
731 (0.9)
1508 (1.8)
502 (0.6)
2741 (3.2)
526 (0.6)
57 (0.1)
80 (0.1)
663 (0.7)
4416 (5.3)
More vs less trials: Proportional effects on MAJOR VASCULAR EVENTS per mmol/L reduction in LDL
cholesterol, by baseline LDL cholesterol
0.5 0.75 1 1.25 1.5
No. of events (% pa)
More statin Less statin Relative risk (CI)
More statinbetter
Less statinbetter
3.5
Total 3837 (4.5) 4416 (5.3)
0.64 (0.47 - 0.86)
<2
2,<2.5
2.5,<3.0
3,<3.5
704 (4.6)
1189 (4.2)
1065 (4.5)
517 (4.5)
303 (5.7)
795 (5.2)
1317 (4.8)
1203 (5.0)
633 (5.8)
398 (7.8)
0.71 (0.52 - 0.98)
0.77 (0.64 - 0.94)
0.81 (0.67 - 0.97)
0.61 (0.46 - 0.81)
0.72 (0.66 - 0.78)
99% or 95% CI
ABSOLUTE BENEFIT: Major Vascular Eventsavoided per 1,000 treated over 5 years
Lancet 2012
5-year benefits and known hazards1
per 1000 patients treated
• Benefits on major vascular events (MVEs):– Low-risk (<1% MVE/year) 8 fewer
– Moderate-risk (1-2% MVE/year) 21 fewer
– High-risk (>2% MVE/year) >45 fewer
• Known hazards:– Myopathy (rhabdomyolysis) 0.5 (0.1) more
– Haemorrhagic stroke 1– 7 more
– Diabetes 5– 15 more
1. Assuming 1.5 mmol/L reduction in LDL cholesterol
Ezetimibe: Background
• Ezetimibe inhibits Niemann-Pick C1-like 1(NPC1L1) protein resulting in reduced cholesterol absorption
• When added to a statin, produces ~20% further reduction in LDL-C, equivalent to about 3 dose doublings of the statin
10 20 30 40 50 60
% Reduction in LDL Cholesterol
0
Statin 10 mg 20
mg
40
mg
80
mg
Statin 10 mg+ Ezetimibe
10 mg
Adding ezetimibe to statin: Equivalent to 3 doublings of the statin dose (avoiding increase in myopathy)
Simvastatin and Ezetimibe in Aortic Stenosis (SEAS)1
• N=1873 with mild AS
• Simvastatin 40mg + ezetimibe 10mg vs placebo
• Mean 1.5 mmol/L in LDL cholesterol
• No effect on composite primary endpoint (which included aortic-valve replacement, CHD, coronary revascularization, ischaemic stroke and heart failure)
• No effect on aortic-valve replacement: HR 1.00; 95% CI, 0.84-1.18; P = 0.97
• Reduction in ischaemic vascular events: HR 0.78; 95% CI, 0.63-0.97; P = 0.02 1Rossebø et al NEJM 2008; 359: 1343-56
Study of Heart and Renal Protection (SHARP)1
• N=9,270 with chronic kidney disease (CKD)
• Simvastatin 20mg + ezetimibe 10mg vs placebo
• Mean 0.85 mmol/L reduction in LDL cholesterol
• Reduction in major atherosclerotic events (nonfatal MI or CHD death, non-haemorrhagic stroke, coronary revascularization): HR 0.83, 95% CI 0.74-0.94; P=0.002
• No significant adverse effects
• No effect on renal disease progression
1Baigent et al Lancet 2011; 359: 1343-56
Patients stabilized post ACS ≤ 10 days:LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx)
Standard Medical & Interventional Therapy
Ezetimibe / Simvastatin
10 / 40 mg
Simvastatin
40 mg
Follow-up Visit Day 30, every 4 months
Duration: Minimum 2 ½-year follow-up (at least 5250 events)
Primary Endpoint: CV death, MI, hospital admission for UA,
coronary revascularization (≥ 30 days after randomization), or stroke
N=18,144
Uptitrated to
Simva 80 mg
if LDL-C > 79
(adapted per
FDA label 2011)
Study Design
*3.2mM
**2.6mM
Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12
90% power to detect
~9% difference
LDL-C and Lipid Changes
1 Yr Mean LDL-C TC TG HDL hsCRP
Simva 69.9 145.1 137.1 48.1 3.8
EZ/Simva 53.2 125.8 120.4 48.7 3.3
Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5
Median Time avg
69.5 vs. 53.7 mg/dL
Primary Endpoint — ITT
Simva — 34.7%
2742 events
EZ/Simva — 32.7%
2572 events
HR 0.936 CI (0.887, 0.988)
p=0.016
Cardiovascular death, MI, documented unstable angina requiring
rehospitalization, coronary revascularization (≥30 days), or stroke
7-year event rates
NNT= 50
IMPROVE-IT vs. CTT: Ezetimibe vs. Statin Benefit
CTT Collaboration.
Lancet 2005; 366:1267-78;
Lancet 2010;376:1670-81.
IMPROVE-IT
Using CTT methods: LDL difference between groups using baseline LDL for Pts without blood
samples. Endpoint of CV Death, MI, stroke or revasc >30days post Rand. Cox HR reported.
Safety — ITT
No statistically significant differences in cancer or muscle- or gallbladder-related events
Simva
n=9077
%
EZ/Simva
n=9067
% p
ALT and/or AST≥3x ULN 2.3 2.5 0.43
Cholecystectomy 1.5 1.5 0.96
Gallbladder-related AEs 3.5 3.1 0.10
Rhabdomyolysis* 0.2 0.1 0.37
Myopathy* 0.1 0.2 0.32
Rhabdo, myopathy, myalgia with CK elevation* 0.6 0.6 0.64
Cancer* (7-yr KM %) 10.2 10.2 0.57
* Adjudicated by Clinical Events Committee % = n/N for the trial duration
Wider implications of IMPROVE-IT
• Consistent with log-linear relationship between LDL cholesterol and CV risk, and previous statin trials
• Suggests other non-statin drugs, when added to statins, may be expected to reduce risk as predicted by the CTT statin data
• Potential for drug combination, eg PCSK-9 inhibitors, ezetimibe, high-dose statin, to yield ~80% ↓ LDL cholesterol
→2/3 reduction in risk of vascular events in a patient with untreated LDL cholesterol of 4 mmol/L)
Conclusions: Maximising benefit in secondary prevention (high-risk)
• Implications of CTT: choose a regimen that produces the largest absolute reduction in LDL cholesterol without unacceptable adverse effects
• High-dose statins are generally well tolerated
• Adding ezetimibe may be appropriate when:
– Risk remains high despite maximum-intensity statin (even if LDL cholesterol is ‘normal’ or ‘low’)
– High-dose statin may bring safety concerns (eg, in CKD)
– Patients cannot tolerate a statin at all, BUT recent studies suggest that this population is actually very small
