ACCP Cardiology PRN Journal Club

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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

Kyle Thorner has no conflicts of interest to disclose. 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 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;371:2072-82 Science 2004;303:(5661):1149

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 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 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):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. 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):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 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):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 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):2387-2397

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):2387-2397

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):2387-2397

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):2387-2397

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):2387-2397

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):2387-2397

Results Tertiary Outcomes Simvastatin Simvastatin- Ezetimibe (n=9067) HR (95% CI) p-Value (NNT) Nonfatal MI 1083 (14.4%) 945 (12.8%) 0.87 (0.8-0.95) 0.002 (63) Ischemic Stroke 297 (4.1%) 236 (3.4%) 0.79 (0.67-0.94) 0.008 (143) Safety Outcomes 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):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 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.

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 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 Torcetrapib (CETP inhibitor) actually cause harm and increased by mortality in ILLUMINATE trial 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 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

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

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