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A look at ezetimibe and the IMPROVE-IT trial
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It is well known that HMG-CoA reductase inhibitors reduce LDL, a surrogate marker in atherosclerotic disease, as well as primary and secondary CHD events, the need for revascularization and ischemic stroke.
These benefits have been observed with each proportional decrease in LDL regardless of baseline LDL measurements, and results are more dramatic in patients with pre-existing CHD than those without baseline disease. Based on these existing data, the National Cholesterol Education Program – Adult Treatment Panel III (ATP-III) recommendations were updated to set a lower LDL goal for patients with baseline CHD or CHD risk-equivalents. In studies comparing high-intensity statin therapy to a lesser-intensity statin, further decreases in vascular death, major vascular events, need for coronary revascularization and nonfatal ischemic strokes were observedand the American Heart Association/American College of Cardiology guidelines recommend intensity of statin therapy by level of atherosclerotic cardiovascular disease (ASCVD) risk. The ACC/AHA guidelines recommend follow-up to ensure that there has been adequate response to therapy.
Unfortunately, high-intensity statins occasionally fall short. Many patients are unable to achieve sufficient LDL reduction, whereas others are able to tolerate high-intensity statins due largely to musculoskeletal symptoms ranging from myalgia to rhabdomyolysis. As a result, additional atherosclerotic CVD-lowering effects have been sought through combination therapy. Trials evaluating nicotinic acid and fibrates both failed to show significant reduction in events when added to baseline statin therapy.
Previous research
Ezetimibe (Zetia, Merck) is an agent that binds to the Niemann-Pick C1-like 1 (NPC1L1) receptor to inhibit intestinal absorption of dietary cholesterol.
In the SEAS trial, simvastatin plus ezetimibe combination therapy lowered serum LDL concentrations significantly, but the only significant outcome results were a decrease in need for CABG and an increased incidence of cancer. In the ENHANCE trial, significant improvements in LDL lowering was observed when ezetimibe was added to simvastatin therapy vs. simvastatin monotherapy, but the change in aortic intimal-medial thickness was not significant. The SANDS trial demonstrated a similar decrease in LDL, but failed to show significant changes in carotid intima-media thickness. The SHARP investigators were able to show a significant decrease in major atherosclerotic events (a composite of nonfatal MI, any cardiac death, stroke or any arterial revascularization) in patients with moderate to severe renal insufficiency. This difference was with combination therapy compared with placebo, so there is uncertainty about whether the benefit was due to statin therapy alone or due to the addition of ezetimibe.
IMPROVE-IT results
The IMPROVE-IT investigators set out to investigate CHD clinical outcomes comparing statin monotherapy with statin plus ezetimibe therapy. It was a randomized, double blind, events-driven trial that enrolled patients hospitalized for ACS (STEMI, non-STEMI or high-risk unstable angina) within the previous 10 days. Participants were required to be aged at least 50 years and have an LDL of at least 50 mg/dL. Maximum baseline LDL concentrations could not exceed 100 mg/dL for those already receiving statin therapy or 125 mg/dL for statin-naive participants. Patients in IMPROVE-IT were randomly assigned simvastatin 40 mg daily plus placebo or ezetimibe 10 mg daily. Initially, the simvastatin dose could be titrated to 80 mg daily if LDL measured greater than 79 mg/dL on two consecutive measurements. However, this requirement was discontinued, and patients taking 80 mg daily for less than 1 year had their dose reduced to 40 mg when the FDA issued a warning regarding unacceptable rhabdomyolysis risk with 80 mg simvastatin.
IMPROVE-IT was an event-driven trial of 5,250 events with a minimum follow-up of 2.5 years and an anticipated enrollment of 18,000 patients. Due to unexpected high enrollment of patients post-STEMI, a subgroup with lower long-term risk of recurrent events, enrollment of this population was capped. Twenty-seven percent of patients in the simvastatin monotherapy group received the 80-mg simvastatin dose, whereas only 6% of patients in the combined group received the higher dose.
The primary efficacy outcome was the composite of CV death, major coronary events or nonfatal stroke. Secondary efficacy outcomes included: the composite of all-cause mortality, major coronary event or stroke; composite of CHD, nonfatal MI or urgent coronary revascularization at least 30 days after randomization; or composite of CV death, nonfatal MI, hospitalization for unstable angina, all revascularizations at least 30 days after randomization or nonfatal stroke. Safety outcomes included liver enzyme levels, creatine kinase levels, episodes of myopathy or rhabdomyolysis, gallbladder-related adverse events and cancer.
Most patients were receiving post-MI guideline-directed medical therapy. There was a large dropout rate of 42% of patients in each group having never experienced one of the events that comprised the composite event rate at a median of 6 years. These patients likely received a nonstudy statin.
The LDL achieved with the simvastatin/ezetimibe combination was 24% lower than simvastatin monotherapy at 1 year (see Table). The primary outcome occurred in 32.7% of those receiving combination therapy vs. 34.7% in the single-therapy group at 7 years (P = .016; number needed to treat = 50). This difference also was observed with the three secondary endpoints as well. Individually, there was a decrease in MI, nonfatal MI, any stroke, ischemic stroke and need for urgent coronary revascularization. The number needed to treat to prevent one MI is 59 and to prevent one stroke is 167. There was no difference in rates of all-cause mortality, CV mortality or CHD. When evaluating the prespecified subgroups, there was particular benefit among patients aged older than 75 years (HR = 0.797; P = .005) and those with diabetes (HR = 0.856; P = .023). There was no interaction between baseline LDL and the primary endpoint. Further, there was no difference in tolerability with either regimen.
This study was performed using simvastatin, and most participants received a dose considered to be moderate intensity. It is uncertain if the same additional decrease in events would be obtained when adding to one of the other high-intensity agents.
A “back-of-the-napkin” pharmacoeconomic analysis of the IMPROVE-IT data suggests that approximately 50 patients need to be treated for 7 years to prevent one atherosclerotic CVD event at an additional cost of about $23,000 (simvastatin/ezetimibe combination therapy [around $9] per day vs. generic moderate-intensity statin or even generic high-intensity statin at approximately 10-15 cents per day [Micromedex Red Book prices]). With current pricing, the combination of ezetimibe and a statin has a lower price per quality-adjusted life year for prevention of major CV events compared with PCSK9 inhibitors. Ezetimibe is anticipated to go generic in late 2016.
Future and current use
To date, ezetimibe is the only agent that has shown an a priori decrease in the rate of major CV events when added onto a background of statin therapy. Emerging data with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have a more dramatic effect on LDL, and exploratory and post hoc analyses of two of these agents suggest a reduced incidence of CV events. The ODYSSEY COMBO trial compared maximally tolerated statin therapy with the addition of ezetimibe or alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals). During a 24-week treatment course, LDL was decreased by 50.6 ± 1.4% with alirocumab vs. only 20.7 ± 1.9% with ezetimibe. Prospective studies evaluating the effects of PCSK9 inhibitors on CV events are not expected to conclude until 2016 to 2017.
Ezetimibe is a relatively inexpensive agent that has been shown to further decrease the rate of major adverse CV events in patients with atherosclerotic CHD. But given recent advances in therapy with the PCSK9 inhibitors, IMPROVE-IT may have been too little too late.
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- For more information:
- Jessie Dunne, PharmD, BCPS, is from the University of Kentucky Healthcare. Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is professor of clinical pharmacy and the residency and industry fellowship programs coordinator at Philadelphia College of Pharmacy at University of the Sciences in Philadelphia. Spinler is the Cardiology Today Pharmacology Consult column editor. She can be reached at Philadelphia College of Pharmacy at University of the Sciences, 600 S. 43rd St., Philadelphia, PA 19104; email: s.spinle@usciences.edu.
Disclosure: Dunne reports no relevant financial disclosures.