ACCP Cardiology PRN Journal Club
1
Announcements • Thank you attending the ACCP Cardiology PRN Journal Club– Thank you if you attended before or have been attending
• I have created a PB Works Site that will house our recorded calls, handouts, and Summary/Q&A documents. The link is https://accpcardsprnjournalclub.pbworks.com/
• If there are any suggestions, please let us know.
Ezetimibe Added to Statin Therapy after Acute Coronary Syndrome (IMPROVE-IT)
Kyle Thorner, Pharm.D.PGY2 Cardiology Resident
WakeMed Health & HospitalsRaleigh, 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).
NEJM 2014;371:2072-82Science 2004;303:(5661):1149
• Mutations in NPC1L1 reduce plasma LDL-C and have been associated with reduced risk of CHD
Background
• Prior clinical trial experience with ezetimibeTrial Treatment Primary Outcome Result
ENHANCESimvastatin/Ezetimibe
80/10 mg vs Simvastatin 80 mg
Mean Δ carotid-artery intima-media thickness
0.0058 mm vs 0.0111 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 (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
NEJM 2008;358(14):1431-1443NEJM 2008;359:1343-1356Lancet 2011;377:2181-2192
*Incidence of cancer: 105 vs 70, p=0.01
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 PopulationInclusion 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
• 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
NEJM 2015;372(25):2387-2397
Study EndpointsPrimary 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• 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)
• 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
NEJM 2015;372(25):2387-2397
Variable Simvastatin(n=9077)
Simvastatin-Ezetimibe(n=9067)
Mean Age, yrs 63.6 63.6Male Sex, % 75.9 75.5White Race, % 84 83.6Mean LDL, mg/dL 93.8 93.8Index EventSTEMI / NSTEMI / UA, % 28.7 / 46.9 / 24.4 28.5 / 47.5 / 24PCI, % 69.7 70.5Medications prior to index ACSStatin, %Aspirin, %
34.342.5
35.641.9
Medications post ACSAspirin, %Thienopyridine, %Beta Blocker, %ACE-Inhibitor or ARB, %
96.986.186.875.8
97.186.687.375.3
Baseline Characteristics
NEJM 2015;372(25):2387-2397
Results1 Yr Mean LDL-C TC TG HDL hsCRPSimva 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= 50Yearly NNT= 350
NEJM 2015;372(25):2387-2397
ResultsTertiary Outcomes Simvastatin
(n=9077)Simvastatin-
Ezetimibe (n=9067)
HR(95% CI)
p-Value(NNT)
Nonfatal MI 1083 (14.4%) 945 (12.8%) 0.87 (0.8-0.95)
0.002(63)
Ischemic Stroke 297 (4.1%) 236 (3.4%) 0.79(0.67-0.94)
0.008(143)
Safety Outcomes Simvastatin(n=9077)
Simvastatin-Ezetimibe (n=9067)
p-Value
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 CritiqueStrengths
• 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
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 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, (0.93-1.16)P=0.52
NEJM 2010;362(17):1563-1574, NEJM 2011;365(24):2255-2267NEJM 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, 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– WakeMed Health & Hospitals
• Craig Beavers, Pharm.D., AACC, BCPS-AQ Cardiology– TriStar Centennial Medical Center
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 e-mail the journal club at [email protected] or [email protected]
• 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
Top Related