Conference Coverage

Ezetimibe’s ACS benefit centers on high-risk, post-CABG patients

Publish date: October 27, 2016

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CABG doesn’t cure systemic atherosclerosis

I suspect that the patients in IMPROVE-IT with a history of coronary artery bypass graft surgery were more likely than the other enrolled acute coronary syndrome patients to have more extensive and systemic atherosclerotic disease. Although coronary artery bypass addresses the most acute obstructions to coronary flow that exist at the time of surgery, the procedure does not cure the patient’s underlying vascular disease. We know that a substantial majority of coronary events occur in arteries that are not heavily stenosed.

Dr. Richard A. Chazal

The results of this analysis show that patients who undergo CABG are not cured of their atherosclerotic disease and require aggressive postoperative medical management. The findings suggest that we should consider patients with a history of bypass to have the highest risk of any acute coronary syndrome patient. You cannot think that patients who have undergone bypass are now covered against additional cardiovascular disease events.

Another important limitation to keep in mind about the IMPROVE-IT trial was that the background statin treatment all patients received was modest – 40 mg of simvastatin daily. In real-world practice, high-risk patients should go on the most potent statin regimen they can tolerate – ideally, 40 mg daily of rosuvastatin. The need for additional lipid-lowering interventions, with ezetimibe or other drugs, can then be considered as an add-on to aggressive statin therapy.

Richard A. Chazal, MD, is an invasive cardiologist and medical director of the Heart and Vascular Institute of Lee Memorial Health System in Fort Myers, Fla. He is also the current president of the American College of Cardiology. He had no disclosures. He made these comments in an interview.

AT THE ESC CONGRESS 2016

ROME – Patients who have undergone coronary artery bypass surgery and who later have an acute coronary syndrome event gain the most from an aggressive lipid-lowering regimen, according to an exploratory analysis of data from more than 18,000 patients enrolled in the IMPROVE-IT trial that tested the incremental benefit from ezetimibe treatment when added to a statin.

Additional exploratory analyses further showed that high-risk acute coronary syndrome (ACS) patients without a history of coronary artery bypass grafting (CABG) also benefited from adding ezetimibe to a background regimen of simvastatin, but the benefit from adding ezetimibe completely disappeared in low-risk ACS patients, Alon Eisen, MD, said at the annual congress of the European Society of Cardiology.

^{Mitchel L. Zoler/Frontline Medical News}

Dr. Alon Eisen

His new analysis of results from the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) study showed that the 10% of patients with a history of CABG prior to the ACS event that got them into the trial had a 9-percentage-point reduction in the incidence of the trial’s primary efficacy endpoint during an average 7 years of follow-up, compared with a 1–percentage point reduction among the other 90% of patients. This translated into a number needed to treat of 11 patients with a history of CABG and a recent ACS event to prevent one cardiovascular disease event over the next 7 years, compared with a number needed to treat of 77 among everyone else in IMPROVE-IT. Coincident with his report at the congress, the results appeared in an article published online (Eur Heart J. 2016 Aug 28. doi: 10.1093/eurheartj/ehw377).

‘The benefit of adding ezetimibe to a statin was enhanced in patients with prior CABG and in other high-risk patients with no prior CABG, supporting the use of more intensive lipid-lowering therapy in these high-risk patients,” said Dr. Eisen, a cardiologist at Brigham and Women’s Hospital in Boston. He also highlighted that ezetimibe is “a safe drug that is coming off patent.” Adding ezetimibe had a moderate effect on LDL cholesterol levels, cutting them from a median of 70 mg/dL in patients in the placebo arm to a median of 54 mg/dL in the group who received ezetimibe.

These results “show that if we pick the right patients, a very benign drug can have a great benefit,” said Eugene Braunwald, MD, a coinvestigator on the IMPROVE-IT trial and a collaborator with Dr. Eisen on the new analysis. The new findings “emphasize that the higher a patient’s risk, the more effect they get from cholesterol-lowering treatment,” said Dr. Braunwald, professor of medicine at Harvard University and a cardiologist at Brigham and Women’s Hospital, both in Boston.

^{Mitchel L. Zoler/Frontline Medical News}

Dr. Eugene Braunwald

The finding may help resolve a conundrum that has surrounded the main IMPROVE-IT finding since the results first came out 2 years ago: Although the incremental benefit from adding ezetimibe therapy was statistically significant, its clinical impact was modest, with a number needed to treat of 50 for 7 years to reduce the incidence of the primary endpoint by one event. “From a clinical point of view, the improvement was pretty small,” admitted Dr. Braunwald during a separate talk at the congress. Targeting ezetimibe to post-CABG and other high-risk patients following an ACS event may be a practice that cardiologists are more willing to embrace.

The second exploratory analysis reported by Dr. Eisen looked at the more than 16,000 patients in IMPROVE-IT without history of CABG. The analysis applied a newly developed, nine-item formula for stratifying atherothrombotic risk (Circulation. 2016 July 26;134[4];304-13) to divide these patients into low-, intermediate- and high-risk subgroups. Patients in the high-risk subgroup (20% of the IMPROVE-IT subgroup) had a 6–percentage point reduction in their primary endpoint event rate with added ezetimibe treatment, while those at intermediate risk (31%) got a 2–percentage point decrease in endpoint events, and low-risk patients (49%) actually showed a small, less than 1–percentage point increase in endpoint events with added ezetimibe, Dr. Eisen reported.

IMPROVE-IT was funded by MERCK, the company that markets ezetimibe (Zetia). Dr. Eisen had no disclosures. Dr. Braunwald has been a consultant to Merck as well as to Bayer, Daiichi Sankyo, The Medicines Company, Novartis, and Sanofi.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

Ezetimibe’s ACS benefit centers on high-risk, post-CABG patients

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