Background and Objective

Lowering low-density lipoprotein cholesterol (LDL-C) has been a principal focus of cardiovascular disease (CVD) prevention. Multiple clinical trials, mostly involving statin medications, have shown significant graded reductions in CVD morbidity and mortality with more intensive LDL-C lowering. However, to date there has been no major clinical trial that has shown further efficacy in CVD event reduction from adding another lipid-modifying therapy to background stain medication. Several trials involving fibrates, niacin, and cholesterylester transfer protein (CETP) inhibitors have failed to show added benefit over background statin therapy. As a result, recent American College of Cardiology (ACC)/American Heart Association (AHA) guidelines have emphasized statin therapy and appropriate statin intensity based on extensive clinical trial evidence; however, many patients on statins do not achieve optimal reductions of LDL-C and/or still suffer CVD events.

The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is the first large clinical trial to evaluate the efficacy of the combination of ezetimibe with simvastatin versus simvastatin alone for reducing CVD events in high risk subjects with a recent acute coronary syndrome (ACS).

Methods

Qualifying patients needed to have: 1) been stabilized for a recent ST-elevation myocardial infarction (STEMI), non–ST-elevation myocardial infarction (NSTEMI)/unstable angina (UA) within 10 days; 2) aged 50 years and over; 3) with at least one additional high-risk factor to include new ST changes, positive troponin, diabetes, prior MI, peripheral artery disease (PAD), cerebrovascular disease, prior coronary artery bypass graft (CABG) over three years ago, or multivessel coronary disease; and 4) have an LDL-C of 50-125 mg/dl (or 50-100 mg/dl if prior lipid lowering therapy). Those who were treated with CABG for their qualifying ACS, on current statin therapy more potent than simvastatin 40 mg, or with creatinine clearance <30 mL/min or active liver disease were not eligible to participate.

18,144 qualifying patients on standard medical and interventional therapy were randomized to either simvastatin 40 mg OR ezetimibe 10 mg in combination with simvastatin 40 mg with subjects titrated to 80 mg simvastatin if LDL-C >79 mg/dl. Subjects received follow-up visits every four months with a minimum duration of follow-up of 2.5 years. The trial was event-driven to accrue a minimum of 5,250 events.

The primary endpoint was CVD death, MI, hospital admission for UA, coronary revascularization at least 30 days after randomization, or stroke.

Results

Overall, there were 5,314 events that occurred over a median six-year follow-up. The mean age of subjects was 64 years, of which 25% were female and 27% with diabetes. 21% had an MI prior to the index ACS. 88% received catheterization or PCI for their ACS event. Mean LDL-C at the ACS event was 95 mg/dl.

After one year of treatment, mean LDL-C was reduced to 69.9 mg/dl in those on simvastatin alone and 53.2 mg/dl in those on the combination treatment for a difference between groups of 16.7 mg/dl. The median time-averaged LDL-C was 69.5 mg/dl and 53.7 mg/dl, respectively. Triglycerides were also 16.7 mg/dl lower, HDL-C 0.6 mg/dl higher, and high-sensitivity C-reactive protein (hs-CRP) 0.5 mg/L lower in the combination treated group.

The seven-year event rate was 34.7% in the simvastatin only group and 32.7% in the combination treated group, or a 2% absolute risk reduction, translating to a number needed to treat of 50 to prevent one CVD event over seven years. The hazard ratio was 0.94 (0.89-0.99) (p = 0.016) indicating a 6% relative risk reduction. Of note, among individual endpoints, while there were no differences in total CVD or unstable angina, significant relative risk reductions of 13% were seen in MI, 21% in ischemic stroke, as well as the combination of CVD, MI, and stroke (10%) with an absolute risk reduction of 1.8% (number needed to treat [NNT] = 56) (all p <0.01). There was a trend towards female and older individuals (aged 65 years and over) faring better, as well as those with diabetes(significant interaction p=0.023). There were no differences in cancer, gallbladder, or muscle-related adverse events between the groups.

Conclusion

The authors concluded that: 1) non-statin add-on therapy with ezetimibe provided further lowering of LDL-C and reduction of CVD events; 2) that further lowering of LDL-C (53 mg/dl vs. 70 mg/dl) was better in lowering CVD events (further supporting the LDL hypothesis); and 3) that the combination therapy was safe.

Commentary/Perspective

The IMPROVE-IT trial provides the first evidence from a large-scale event-driven randomized clinical trial that additional lipid modifying therapy further lowering LDL-C provides further CVD event reduction beyond statin therapy alone in high-risk ACS patients.

It important, however, to remember that the trial was done in exclusively high-risk persons with a recent ACS so may not apply to lower risk persons; thus, the implications of this trial beyond the study population and the NNT values should be generalized with caution. While the relative risk reduction of 6% (hazard ratio of 0.94) would not generally be thought as very impressive, IMPROVE-IT did note a reasonable NNT of 50 in a high-risk population to prevent a CVD event; thus, such added therapy would seem to be a reasonable option for high-risk subjects with ACS. The somewhat greater relative risk reductions in MI and, in particular, ischemic stroke are encouraging. However, in lower risk subjects where the absolute event rates would be a fraction of the observed ~5% annual event rate in IMPROVE-IT, the absolute reduction in events would be much smaller (and, thus, NNT much higher) Therefore, the results of this trial would not immediately support routine use of this combination in primary prevention unless the baseline risks are clearly very high (e.g., long-standing diabetes with multiple risk factors or advanced subclinical coronary atherosclerosis).

The trial does support the concept that a lower LDL-C is better when using ezetimibe to go from 70 mg/dl to about 53 mg/dl in this patient population; however, the results should not be extrapolated to mean that such an LDL-reduction at any level of baseline LDL-C (or with any LDL lowering drug) would necessarily translate to a similar event reduction. Thus, in persons already on a high-intensity statin and at an LDL-C of 55, for instance, the magnitude of event reduction with the addition of ezetimibe would be uncertain. Finally, while clearly supporting the LDL hypothesis, we have to ask whether the observed event reduction was exclusively due to further lowering in LDL-C, or whether the further lowering of triglycerides or even hs-CRP observed in this study may have contributed to some of the effect. Examination of any resultant changes in LDL particle number and differences between groups will be of interest to examine.

The current ACC/AHA guideline for cholesterol management does note that in high-risk patients who do not achieve the expected therapeutic reduction in LDL-C from a high-intensity statin, are unable to tolerate the recommended intensity of a statin, or who are statin intolerant could be considered for a non-statin drug that has been shown in randomized controlled trials to show benefits that outweigh the risks. The IMPROVE-IT trial can, thus, be incorporated into the current guidelines as providing clear evidence that ezetimibe should be the next drug of choice in statin-treated ACS patients.

References

0.  
1. Cannon CP. Improve-IT Late Breaker Clinical Trial Slides (Clinical Trial Results website). 1999-2009. Available at: http://clinicaltrialresults.org/Slides/AHA2014/Cannon_IMPROVEIT.ppt. Accessed 12/16/14.

Keywords: Acute Coronary Syndrome, American Heart Association, Angina, Unstable, Azetidines, Catheterization, Cholesterol, LDL, Coronary Artery Bypass, Coronary Artery Disease, C-Reactive Protein, Creatinine, Diabetes Mellitus, Drug Combinations, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipoproteins, LDL, Myocardial Infarction, Peripheral Arterial Disease, Simvastatin, Stroke, Triglycerides, Troponin, American Heart Association, Arrhythmias, Cardiac, Benchmarking, Cardiac Surgical Procedures, Cardiac Tamponade, Catheter Ablation, Centers for Medicare and Medicaid Services, U.S., Consensus, Cost of Illness, Credentialing, Electrophysiologic Techniques, Cardiac, Patient Care, Physicians

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