ACCP Cardiology PRN Journal Club
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Announcements
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Ezetimibe Added to Statin
Therapy after Acute Coronary
Syndrome (IMPROVE-IT)
Kyle Thorner, Pharm.D.
PGY2 Cardiology Resident
WakeMed Health & Hospitals
Raleigh, NC
Disclosure Statement
Kyle Thorner has no conflicts
of interest to disclose.
Background
• Ezetimibe inhibits the absorption of LDL-C
from the intestinal lumen via inhibition of
Niemann-Pick C1 (NPC1L1).
• Mutations in NPC1L1
reduce plasma LDL-C
and have been
associated with
reduced risk of CHD
NEJM 2014;371:2072-82
Science 2004;303:(5661):1149
Background
• Prior clinical trial experience with ezetimibe
Trial
Treatment
Primary Outcome
Result
ENHANCE
Simvastatin/Ezetimibe
80/10 mg vs Simvastatin
80 mg
SEAS
Simvastatin/Ezetimibe
40/10 mg vs Placebo
Composite of major
cardiovascular events
35.5% vs 38.2%; HR
0.96 (0.83-1.12),
p=0.59*
SHARP
Simvastatin/Ezetimibe
20/10 mg vs Placebo
First major
atherosclerotic event
13.4% vs 11.3%; RR
0.83 (0.74-0.94),
p=0.0021
Mean Δ carotid-artery
0.0058 mm vs
intima-media thickness 0.0111 mm, p=0.28
*Incidence of cancer: 105 vs 70, p=0.01
NEJM 2008;358(14):1431-1443
NEJM 2008;359:1343-1356
Lancet 2011;377:2181-2192
IMPROVE-IT Study Objective
To evaluate the effect of ezetimibe combined
with simvastatin, as compared with that of
simvastatin alone, in stable patients who had
had an acute coronary syndrome and whose LDL
cholesterol values were within guideline
recommendations.
NEJM 2015;372(25):2387-2397
Study Population
Inclusion Criteria
Exclusion Criteria
- Age ≥ 50 years
- Hospitalization within
previous 10 days for ACS
- LDL cholesterol ≥ 50 mg/dL
- LDL ≤125 mg/dL for patients
naïve to lipid-lowering
therapy
- LDL ≤100 mg/dL for patients
on lipid-lowering therapy
-
Planned CABG
CrCl < 30 ml/min
Active liver disease
Use of statin therapy with
LDL-lowering potency
greater than 40 mg of
simvastatin
NEJM 2015;372(25):2387-2397
Study Design
• International, multi-center, double-blind, placebo-controlled,
randomized trial
Simvastatin 40* mg +
Placebo daily
(n=9077)
18,144 patients
Simvastatin 40* mg +
Ezetimibe 10mg daily
*Simvastatin could be
uptitrated to 80 mg if
LDL-C >79 mg/dL,
addendum made after
FDA advisory in 2011
(n=9067)
• Follow-Up
– Visits: At 30 days, 4 months and every 4 months thereafter
– Blood Samples: at randomization, at 1, 4, 8, and 12 months, and
then yearly
NEJM 2015;372(25):2387-2397
Study Endpoints
Primary Endpoint
• Composite of death from CVD, major coronary
event, or nonfatal stroke
Safety Endpoints
•
•
•
•
•
Liver enzyme levels
CK levels
Episodes of myopathy or rhabdomyolysis
Gallbladder-related adverse events
Cancer
NEJM 2015;372(25):2387-2397
Statistics & Enrollment
Statistics
Enrollment
• Estimated that 5,250 events
required for 90% power to
detect a 9.375% lower
relative risk for the primary
end point with simvastatinezetimibe vs simvastatin
• Intention-to-treat analysis
•
•
•
•
N = 18,144
Median follow-up = 6 years
Total follow-up = 7 years
Regions:
–
–
–
–
–
North America (N=6,973)
Western Europe (N=7,274)
Eastern Europe (N=1,416)
Asia Pacific (N=896)
South America (N=1,585)
NEJM 2015;372(25):2387-2397
Baseline Characteristics
Simvastatin
Simvastatin-Ezetimibe
(n=9077)
(n=9067)
Mean Age, yrs
63.6
63.6
Male Sex, %
75.9
75.5
84
83.6
93.8
93.8
28.7 / 46.9 / 24.4
28.5 / 47.5 / 24
PCI, %
69.7
70.5
Medications prior to index ACS
Statin, %
Aspirin, %
34.3
42.5
35.6
41.9
Medications post ACS
Aspirin, %
Thienopyridine, %
Beta Blocker, %
ACE-Inhibitor or ARB, %
96.9
86.1
86.8
75.8
97.1
86.6
87.3
75.3
Variable
White Race, %
Mean LDL, mg/dL
Index Event
STEMI / NSTEMI / UA, %
NEJM 2015;372(25):2387-2397
Results
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
Simva
EZ/Simva
NEJM 2015;372(25):2387-2397
Results
Total NNT= 50
Yearly NNT= 350
NEJM 2015;372(25):2387-2397
Results
Tertiary Outcomes
Simvastatin
(n=9077)
SimvastatinEzetimibe
(n=9067)
HR
(95% CI)
p-Value
(NNT)
Nonfatal MI
1083 (14.4%)
945 (12.8%)
0.87 (0.80.95)
0.002
(63)
Ischemic Stroke
297 (4.1%)
236 (3.4%)
0.79
(0.67-0.94)
0.008
(143)
Simvastatin
SimvastatinEzetimibe
Safety Outcomes
(n=9077)
p-Value
(n=9067)
ALT, AST, or both ≥3 ULN
208 (2.3%)
224 (2.5%)
0.43
Rhabdomyolysis
18 (0.2%)
13 (0.1%)
0.37
Myopathy
10 (0.1%)
15 (0.2%)
0.32
Cancer
732 (10.2%)
748 (10.2%)
0.57
NEJM 2015;372(25):2387-2397
Author’s Conclusion
The addition of ezetimibe to statin therapy
in stable patients with recent ACS and who
had LDL cholesterol levels within guideline
recommendations further lowered the risk
of cardiovascular events.
NEJM 2015;372(25):2387-2397
Study Critique
Strengths
Weaknesses
• Large sample size with
long duration of
follow-up
• Low incidence of
adverse effects with
simvastatin/ezetimibe
• Age subgroup analysis
comparable to
modern guidelines
• Intensity of statin
therapy does not
reflect current
guideline
recommendations
• Amount of study drug
discontinuation
• Modest benefit and
primarily in nonfatal
endpoints
Impact on Clinical Practice
• First clinical trial to show benefit on composite CV
outcome when adding non-statin therapy to a statin.
Trial
Treatment
Primary Outcome
Result
The ACCORD
Study Group
Simvastatin +
Fenofibrate/Placebo
Nonfatal MI/Nonfatal
stroke/CV death
HR 0.92 (0.79-1.08)
P=0.32
AIM-HIGH
Simvastatin +/- Ezetimibe
+ Niacin/Placebo
Nonfatal MI/Ischemic
Stroke/ACS hospitalization/
Revascularization/CV death
Stopped early due
to lack of efficacy
HPS2-THRIVE
Simvastatin +/- Ezetimibe
+ Niacin/Placebo
Time to first major vascular
event
RR 0.96 (0.90-1.03)
P=0.29
The dalOUTOMES
Investigators
Dalcetrapib vs placebo in
addition to standard of
care (98% statins)
CHD death, nonfatal MI,
ischemic stroke, unstable
angina, cardiac arrest
HR 1.04, (0.93-1.16)
P=0.52
NEJM 2010;362(17):1563-1574, NEJM 2011;365(24):2255-2267
NEJM 2014;371(3):203-212, NEJM 2012;367(22):2089-2099
Impact on Clinical Practice
• May support the LDL hypothesis, but does not
disprove the statin hypothesis.
– Reconsider LDL-C targets in future guidelines
– Future study: High intensity statin compared to
ezetimibe/simvastatin with equal LDL lowering
• Could apply results to justify addition of
ezetimibe to moderate intensity statin therapy
– Patients intolerant of high-intensity statins
– Elderly patients
– Diabetic patients
Acknowledgements
• Dave L. Dixon, Pharm.D., AACC, FNLA, CDE, CLS, BCPSAQ Cardiology
– Virginia Commonwealth University School of Pharmacy
• Erin (Allender) Ledford, Pharm.D., BCPS-AQ Cardiology
– WakeMed Health & Hospitals
• Janna Beavers, Pharm.D., BCPS
– WakeMed Health & Hospitals
• Craig Beavers, Pharm.D., AACC, BCPS-AQ Cardiology
– TriStar Centennial Medical Center
Questions?
Thank you for attending!
• If you would like to have your resident present,
would like to be a mentor, or have questions or
comments please e-mail the journal club at
accpcardsprnjournalclub@gmail.com or
craig.beaverspharmd@gmail.com
• Join us next month when we hear the BRIDGE
Trial from Leah Sabato, PharmD PGY-2 Cardiology
from Vanderbilt with Michael Gulseth , PharmD
as mentor
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