1. ACCP Cardiology PRN Journal Club

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3. Ezetimibe Added to Statin Therapy after Acute Coronary Syndrome (IMPROVE-IT)
Kyle Thorner, Pharm.D.
PGY2 Cardiology Resident
WakeMed Health & Hospitals
Raleigh, NC

4. Kyle Thorner has no conflicts of interest to disclose.
Disclosure Statement
Kyle Thorner has no conflicts of interest to disclose.

5. 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
Ezetimibe lowers LDL-C by ~20% via inhibition of Niemann-Pick transportation of dietary cholesterol from the intestinal lumen.
NEJM 2014 – ~20,000 pts, 1 in every 650 people heterozygous for inactivating mutation  lowered LDL-C by 12mg/dL and associated with 53% relative reduction in risk of CHD
NEJM 2014;371:
Science 2004;303:(5661):1149

6. Background Prior clinical trial experience with ezetimibe ENHANCE
Treatment
Primary Outcome
Result
ENHANCE
Simvastatin/Ezetimibe 80/10 mg vs Simvastatin 80 mg
Mean Δ carotid-artery intima-media thickness
mm vs mm, p=0.28
SEAS
Simvastatin/Ezetimibe 40/10 mg vs Placebo
Composite of major cardiovascular events
35.5% vs 38.2%; HR 0.96 ( ), p=0.59*
SHARP
Simvastatin/Ezetimibe 20/10 mg vs Placebo
First major atherosclerotic event
13.4% vs 11.3%; RR 0.83 ( ), p=0.0021
ENHANCE- ~700 pts w/ familial hypercholesterolemia, significantly lowered LDL cholesterol but produced no difference in surrogate clinical endpoint of IMT
SEAS – ~1800 Pts w/ mild-to-moderate aortic stenosis, no reduction in CV outcomes, concern arised for increased risk of cancer w/ ezetimibe (105 vs 70, p=0.01)
SHARP – ~9400 Pts w/ CKD, combo showed reduction in primary endpoint compared to placebo
No evidence that to this point that addition ezetimibe or any non-statin therapy to a statin provides benefit in clinical outcomes when added to statin therapy
*Incidence of cancer: 105 vs 70, p=0.01
NEJM 2008;358(14):
NEJM 2008;359:
Lancet 2011;377:

7. 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.
Does the addition ezetimibe provide additional outcome benefit?
Is lower even better (just simvatsatin arm predicted to get LDL to 65, addition of ezetimibe to 50)
Is ezetimibe safe?
NEJM 2015;372(25):

8. 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
ACS = An acute MI, with or without ST-segment elevation on ECG, or high risk UA
LDL lvl for eligibility measured with the first 24 hrs of onset of ACS – lipid lvls during ACS decreased after an index event and can remain for 2-3 months
Why crcl <30?
Supplementary
Inclusion
Any sex or race
Pts w/ qualifying ACS event (3) with planned PCI management prior to randomization and within 10 days of initial hospitalization for the event.
NSTE-ACS or STEMI:
A NSTE-ACS subject participating in the EARLY-ACS Study who had been clinically stabalized was eligible . Had to have completed the 96-hr primary endpoint of the acute segment of EARLY-ACS treatment
2) Subjects not participating in EARLY-ACS, but defined as NSTE-ACS by meeting all of the following criteria and were clinically stable for at least 24 hrs prior to screening or randomization, were eligilbe to enter directly into the current study </= 10 days of acute admittance:
-Subject experience sx of ischemia
-50 yrs of age
-ANY 1 of the following: ECG changes (New ST-segment depression>/= 0.1 mV in at least 2 contiguous leasds or transient (<30 min) ST-segment elevation >/= 0.1 V in at least 2 contiguous leads, Elevated biomarkers, diabetes, hx MI, PAD, cerebrovascular disease, CABG >/= 3 yrs ago, multivessel CAD
3) A subject who had been clinically stable for at least 24 hours following a high-risk STEMI as defined by the following criteria may have been enrolled in the current study within 10 days of acute admittance into a hospital:
1)  The subject has experienced symptoms of cardiac ischemia at rest with at least one
episode lasting at least 30 minutes in conjunction with the clinical event prompting
hospitalization; and
2)  The subject must have all three of the following:
-New or presumably new electrocardiogram (ECG) changes characterized by any of
the following:
[1]  Persistent ST-segment elevation ≥0.1 mV in at least 2 contiguous ECG leads;
[2]  Pathologic Q waves in at least 2 contiguous ECG leads; or Left bundle branch
block (LBBB).
Any of the following biomarkers elevated >ULN:
[1]  Troponin I;
[2]  Troponin T; and/or
[3]  CK-MB.
One of the following characteristics:
[ 1]  Presence of an acute anterior ST-elevation myocardial infarction; or
[ 2]  ≥50 years of ag e
NEJM 2015;372(25):

9. Study Design
International, multi-center, double-blind, placebo-controlled, randomized trial
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
18,144 patients
Simvastatin 40* mg + Placebo daily
(n=9077)
Simvastatin 40* mg + Ezetimibe 10mg daily
(n=9067)
*Simvastatin could be uptitrated to 80 mg if LDL-C >79 mg/dL, addendum made after FDA advisory in 2011
More potent therapy could be initiated if LDL > 100 mg/dL
EARLY ACS trial: timing of integrelin before or after angiography in patients with non STEMI ACS
Stratification
Prior use of lipid-lowering therapy
Type of ACS
Enrollment status in concurrent EARLY ACS trial
NEJM 2015;372(25):

10. Study Endpoints Primary Endpoint Safety Endpoints
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
Primary Efficacy Endpoint
Composite of death from CVD, major coronary event, or nonfatal stroke
Secondary Efficacy Endpoints
Composite of death from any cause, major coronary event, or nonfatal stroke
Composite of death from CHD, nonfatal MI, or urgent coronary revascularization 30 days or more after randomization
Composite of death from cardiovascular cause, nonfatal MI, hospitalization for UA, all revascularization 30 days after randomization, or nonfatal stroke.
NEJM 2015;372(25):

11. 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 simvastatin-ezetimibe 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):

12. Baseline Characteristics
Variable
Simvastatin
(n=9077)
Simvastatin-Ezetimibe
(n=9067)
Mean Age, yrs
63.6
Male Sex, %
75.9
75.5
White Race, % 84
83.6
Mean LDL, mg/dL
93.8
Index Event
STEMI / NSTEMI / UA, %
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
Thienopyridine, %
Beta Blocker, %
ACE-Inhibitor or ARB, %
96.9
86.1
86.8
75.8
97.1
86.6
87.3
75.3
Mean Age = 63.6 yrs
Male sex = ~75%
White race = ~84%
Previous MI (~21%), Previous PCI (~19%), previous CABG (9.3%)
Index event
STEMI (~28.6%), NSTEMI (~47%), UA (~24.2%)
Other medications after event
Aspirin (97%), Thienopyridine (86.4%), BB (87%), ACE/ARB (75.5%)
NEJM 2015;372(25):

13. Results Simva EZ/Simva 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
+0.6
-0.5
Simva
EZ/Simva
Reduction in LDL shown since may pertain to supporting LDL hypothesis
Measurement of LDL difference
Baseline lvl at Index event measure _____????
NEJM 2015;372(25):

14. Results Total NNT= 50 Yearly NNT= 350 Over 7 year follow up
State that Primary Outcome of CV death / major coronary event (non fatal MI, coronary revasc, UA req hosp) / Nonfatal Stroke was driven by non-fatal MI
NEJM 2015;372(25):

15. Results Tertiary Outcomes Simvastatin Simvastatin- Ezetimibe (n=9067)HR
(95% CI)
p-Value
(NNT)
Nonfatal MI
1083 (14.4%)
945 (12.8%)
0.87 ( )
0.002
(63)
Ischemic Stroke
297 (4.1%)
236 (3.4%)
0.79
( )
0.008
(143)
Safety Outcomes
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
Endpoints that drove the primary outcome listed
Pertinent safety outcomes
NEJM 2015;372(25):

16. 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):

17. Study Critique Strengths
Large sample size with long duration of follow-up
Low incidence of adverse effects with simvastatin/ezetimibe
Age subgroup analysis comparable to modern guidelines
Weaknesses
Intensity of statin therapy does not reflect current guideline recommendations
Amount of study drug discontinuation
Modest benefit and primarily in nonfatal endpoints
Of patients who had final study visits.
~42% of patients in the simvastatin monotherapy arm were no longer taking simva 40.
~42% of patients in the simva/ezet arm were no longer on this regimen.

18. 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 ( ) 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
Time to first major vascular event
RR 0.96 ( )
P=0.29
The dal-OUTOMES 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, ( )
P=0.52
Torcetrapib (CETP inhibitor) actually cause harm and increased by mortality in ILLUMINATE trial
NEJM 2010;362(17): , NEJM 2011;365(24):
NEJM 2014;371(3): , NEJM 2012;367(22):

19. 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
BIG question? Can we apply these results to the entire population or only specifically to patients post-ACS
NNT 12 for age >75, NNT 19 for DM
DM pts with ASCVD risk 7.5  high

20. Acknowledgements
Dave L. Dixon, Pharm.D., AACC, FNLA, CDE, CLS, BCPS-AQ Cardiology
Virginia Commonwealth University School of Pharmacy
Erin (Allender) Ledford, Pharm.D., BCPS-AQ Cardiology
WakeMed Health & Hospitals
Janna Beavers, Pharm.D., BCPS
Craig Beavers, Pharm.D., AACC, BCPS-AQ Cardiology
TriStar Centennial Medical Center

21. Questions?

22. 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 the journal club at or
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