IMProved Reduction of Outcomes: Vytorin Efficacy International Trial - IMPROVE-IT

Oct 04, 2021
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Presenter/Author:
Alon Eisen, MD
Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Merck
Date Presented:
08/28/2016
Date Published:
10/04/2021
Date Updated:
10/04/2021
Original Posted Date:
08/29/2016
References

Contribution To Literature:

Highlighted text has been updated as of October 4, 2021.

The IMPROVE-IT trial showed that in high-risk post-acute coronary syndrome (ACS) patients, ezetimibe 10 mg/simvastatin 40 mg was superior to simvastatin 40 mg alone in reducing long-term CV events.

Description:

Although low-density lipoprotein (LDL) lowering has been the mainstay of therapy for primary and secondary cardiovascular (CV) prevention, the data have been primarily for statins. Other nonstatin agents such as fibrates, niacin, and high-density lipoprotein (HDL)-raising agents have all failed to show a clinical benefit when added to statins. The current trial sought to study the safety and efficacy of ezetimibe/simvastatin compared with simvastatin alone in reducing CV events in patients at high risk.

Study Design

  • Placebo-controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Hospitalization for STEMI, NSTEMI/UA <10 days
  • Age ≥50 years
  • ≥1 high-risk feature: new ST changes, positive troponin, diabetes mellitus (DM), prior MI, peripheral arterial disease, cerebrovascular accident, prior coronary artery bypass grafting (CABG) >3 years, and/or multivessel coronary artery disease
  • LDL-C 50-125 mg/dl (50-100 mg/dl if prior lipid-lowering therapy)

    Number of enrollees: 18,144
    Duration of follow-up: 6 years (median) 
    Mean patient age: 64 years
    Percentage female: 25%

Exclusions:

  • CABG for treatment of qualifying ACS
  • Current statin treatment more potent than simvastatin 40 mg
  • Creatinine clearance <30 ml/min
  • Active liver disease

Primary Endpoints:

  • CV death, MI, hospital admission for UA, coronary revascularization (≥30 days after randomization), or stroke

Drug/Procedures Used:

Patients with recent ACS were randomized in a 1:1 fashion to either ezetimibe 10 mg/simvastatin 40 mg or simvastatin 40 mg.

Principal Findings:

A total of 18,144 patients were randomized at 1,158 sites in 39 countries, 9,067 to ezetimibe/simvastatin and 9,077 to simvastatin alone. Baseline characteristics were fairly similar between the two arms. Approximately 27% had DM and 21% had a history of prior myocardial infarction (MI). Presentation was ST-segment elevation MI (STEMI) in 29%, NSTEMI in 47%, and unstable angina (UA) in 24%. Nearly 88% underwent diagnostic angiography and 70% underwent percutaneous coronary intervention. Uptitration to 80 mg simvastatin occurred in 27% of the simvastatin arm and 6% of the ezetimibe/simvastatin arm. Premature discontinuation was observed in 42% of patients in both arms.

Baseline LDL cholesterol (LDL-C) levels were 95 mg/dl in both arms; the median follow-up average was 53.7 mg/dl versus 69.5 mg/dl in the ezetimibe/simvastatin and simvastatin arms, respectively. LDL lowering was observed as early as 1 month, and appeared sustained over the duration of follow-up. At 1 year, triglycerides were also lowered by 16.7 mg/dl in the combination arm, while HDL was increased by 0.6 mg/dl. The primary endpoint of CV death/MI/UA/coronary revascularization beyond 30 days/stroke was significantly lower in the ezetimibe/simvastatin arm compared with the simvastatin arm over the duration of follow-up (32.7% vs. 34.7%, hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.89-0.99; p = 0.016). This corresponded to a number needed to treat (NNT) of 50 patients to prevent one event.

Other endpoints including MI (13.1% vs. 14.8%, p = 0.002), stroke (4.2% vs. 4.8%, p = 0.05), ischemic stroke (3.4% vs. 4.1%, p = 0.008), and CV death/MI/stroke (20.4% vs. 22.2%, p = 0.003) were all significantly lower in the ezetimibe/simvastatin arm; no differences were noted for all-cause mortality (15.4% vs. 15.3%, p = 0.78), CV mortality (6.9% vs. 6.8%, p = 0.99), and need for coronary revascularization (21.8% vs. 23.4%, p = 0.11). On subgroup analysis, patients with DM had a greater benefit with ezetimibe/simvastatin (HR = 0.86, p for interaction = 0.023). On-treatment analysis confirmed and further embellished the primary intention-to-treat analyses; the primary endpoint was significantly reduced in the ezetimibe/simvastatin arm compared with placebo (29.8% vs. 32.4%, HR 0.92, 95% CI 0.87-0.98, p = 0.012; NNT = 38).

No differences were observed in cancer incidence (10.2% vs. 10.2%, p = 0.57), myopathy (0.2% vs. 0.1%, p = 0.32), or transaminitis (2.5% vs. 2.3%, p = 0.43).

Treatment effect in DM: Median change in LDL compared with baseline at 1 year for ezetimibe vs. placebo in DM vs. no DM: 17 vs. 18 mg/dl (p for interaction = 0.58). Primary endpoint for ezetimibe vs. placebo in DM: 40.0% vs. 45.5%; HR 0.85, 95% CI 0.78-0.94; in non-DM: 30.2% vs. 30.8%, HR 0.98, 95% CI 0.91-1.04; p for interaction = 0.023. Similarly, MI for DM: 16.4% vs. 20.8%, for non-DM: 12.0% vs. 12.7%, p = 0.028; stroke for DM: 3.8% vs. 6.5%, for non-DM: 3.2% vs. 3.4%, p = 0.031.

New-onset DM: Similar between the ezetimibe/simvastatin vs. simvastatin arms (HR 1.04, 95% CI 0.94-1.15, p = 0.46). Results were insensitive to different definitions of new-onset DM.

Post-CABG patients: 9.3% had prior CABG. Primary endpoint for patients with and without CABG: 55.6% vs. 31.6%, p < 0.0001. Primary endpoint for ezetimibe vs. placebo: 51.2% vs. 60.0%, HR 0.80, 95% CI 0.69-0.92 (p for interaction = 0.02). Reductions noted for MI: 26.2% vs. 35.3, p < 0.05 and coronary revascularization ≥30 days: 29.2% vs. 37.3%, p < 0.05. 

Safety of achieving very low LDL levels: Patients with LDL-C <30 mg/dl at 1 month were more likely randomized to ezetimibe/simvastatin (85%), had lower baseline LDL-C values, and were more likely older, male, nonwhite, diabetic, overweight, statin naive, and presenting with a first myocardial infarction. After multivariate adjustment, there was no significant association between achieved LDL-C level and any of the nine prespecified safety events. The adjusted risk of the primary efficacy composite was significantly lower in patients achieving an LDL-C level <30 mg/dl at 1 month (adjusted HR 0.79, 95% CI 0.69-0.91; p = 0.001) compared with ≥70 mg/dl.

Stroke risk: There was a significant reduction in ischemic strokes with ezetimibe/simvastatin compared with simvastatin alone (3.4% vs. 4.1%, HR 0.79, 95% CI 0.67-0.94, p = 0.008), with a numerical increase in hemorrhagic strokes (0.8% vs. 0.6%, p = 0.11); all strokes were borderline lower (4.2% vs. 4.8%, p = 0.052). Total strokes (initial and recurrent) were reduced with ezetimibe/simvastatin (p = 0.029). Patients who had experienced a stroke prior to randomization were at a higher risk of recurrence and had a higher absolute risk reduction in all strokes (10.2% vs. 18.8%, NNT = 12, HR 0.60, 95% CI 0.38-0.95, p = 0.030) and ischemic strokes (8.7% vs. 16.3%, NNT = 13, HR 0.52, 95% CI 0.31-0.86, p = 0.011).

Effect of baseline LDL-C: Absolute reduction in LDL-C at 4 months between treatment arms was 17 mg/dl in patients with baseline LDL-C of 50-<70 mg/dl, 20 mg/dl in those with 70-<100 mg/dl, and 19 mg/dl in those with 100-125 mg/dl (pinteraction = 0.64). The effect of ezetimibe/simvastatin vs. placebo/simvastatin on the primary endpoint was consistent regardless of baseline LDL-C of 50-<70 mg/dl (HR 0.92 [95% CI 0.80-1.05]), 70-<100 mg/dl (HR 0.93 [95% CI 0.87-1.01]), or 100-125 mg/dl (HR 0.94 [95% CI 0.86-1.03]; pinteraction = 0.95). No differences in safety endpoints were noted.

Interpretation:

The results of the landmark IMPROVE-IT trial indicate that in patients post high-risk ACS, ezetimibe 10 mg/simvastatin 40 mg is superior to simvastatin 40 mg alone in reducing CV events. A reduction was observed in first as well as recurrent events. Patients with DM, prior stroke, and prior CABG appeared to have a greater treatment effect than patients without DM. Benefit was noted irrespective of baseline LDL-C levels, including among those with LDL-C <70 mg/dl at baseline. Interestingly, there was no increase in the incidence of new-onset DM, as observed with statin therapy. This is the first study powered for clinical outcomes to show a benefit with a nonstatin agent when added to a statin.

This trial included patients who had an LDL-C of <125 mg/dl at the time of ACS, in keeping with the ability of simvastatin and ezetimibe/simvastatin to achieve an LDL-C of <70 mg/dl, based on prevailing lipid guidelines at the time of its design.

The other interesting findings in this trial are that it reaffirms the “lower is better” hypothesis with LDL-C (and with a non-statin approach), with mean levels of LDL-C <60 mg/dl in the combination arm. Thus, there appears to be a direct correlation between degree of benefit and efficacy of LDL-C lowering. Reduction to even very low levels (<30 mg/dl) appeared to be safe; these patients in fact also had the lowest event rates. Similarly, benefits were maintained irrespective of baseline LDL-C levels. Future guidelines will need to factor in the findings of this trial in patients requiring lipid therapy for secondary prevention.

References:

Oyama K, Giugliano RP, Blazing MA, et al. Baseline Low-Density Lipoprotein Cholesterol and Clinical Outcomes of Combining Ezetimibe With Statin Therapy in IMPROVE-IT. J Am Coll Cardiol 2021;78:1499-507.

Editorial Comment: Bittner V. Treatment Thresholds and ASCVD Risk. J Am Coll Cardiol 2021;78:1508-10.

Giugliano RP, Cannon CP, Blazing MA, et al., on behalf of the IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) Investigators. Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With vs. Without Diabetes: Results from IMPROVE-IT. Circulation 2018;137:1571-82.

Bohula EA, Wiviott SD, Giugliano RP, et al. Prevention of Stroke With the Addition of Ezetimibe to Statin Therapy in Patients With Acute Coronary Syndrome in IMPROVE-IT. Circulation 2017;136:2440-50.

Giugliano RP, Wiviott SD, Blazing MA, et al. Long-Term Safety and Efficacy of Achieving Very Low Levels of Low-Density Lipoprotein Cholesterol: A Prespecified Analysis of the IMPROVE-IT Trial. JAMA Cardiol 2017;2:547-55.

Eisen A, Cannon CP, Blazing MA, et al. The benefit of adding ezetimibe to statin therapy in patients with prior coronary artery bypass graft surgery and acute coronary syndrome in the IMPROVE-IT trial. Eur Heart J 2016;37:3576-84.

Presented by Dr. Alon Eisen at the European Society of Cardiology Congress, Rome, Italy, August 28, 2016.

Murphy SA, Cannon CP, Blazing MA, et al. Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome: The IMPROVE-IT Trial. J Am Coll Cardiol 2016;67:353-31.

Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy After Acute Coronary Syndromes. N Engl J Med 2015;372:2387-97.

Presented by Dr. Christopher Cannon at the American Heart Association Scientific Sessions, Chicago, IL, November 17, 2014.

Presented by Dr. Michael A. Blazing at the American Heart Association Scientific Sessions, Chicago, IL, November 18, 2014.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Vascular Medicine, Angiography, Nuclear Imaging

Keywords: Coronary Artery Disease, Myocardial Infarction, Acute Coronary Syndrome, Stroke, Neoplasms, Cholesterol, LDL, Angina, Unstable, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Peripheral Arterial Disease, Simvastatin, Percutaneous Coronary Intervention, Drug Combinations, Azetidines, Niacin, Coronary Artery Bypass, Triglycerides, Lipoproteins, HDL, Muscular Diseases, Diabetes Mellitus, Angiography


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