The combination of ezetimibe and a moderate-intensity statin after coronary stenting may be safer and more clinically effective than monotherapy with a high-intensity statin, suggests a “real-world” cohort study that is consistent with trial evidence.

In the observational study with more than 273,000 patients who received percutaneous coronary intervention (PCI) with drug-eluting stents (DES), risk for a broad composite clinical primary endpoint fell by one-fourth (P < .001) among those put on the two-drug regimen with a moderate-intensity statin compared with those getting a high-intensity statin alone.

The dual-agent approach was also associated with a 15% drop in statin discontinuation and a 20% reduced risk for new-onset diabetes requiring medication (P < .001 for both benefits), reported investigators July 24 in the Journal of the American College of Cardiology.

The study’s primary endpoint — a composite of cardiovascular (CV) death, myocardial infarction (MI), coronary revascularization, heart failure (HF) hospitalization, or nonfatal stroke at 3 years — replicated that of the randomized RACING trial conducted by many of the same researchers and published about a year ago in The Lancet.

RACING concluded that ezetimibe plus a moderate-intensity statin could be as effective as a high-intensity statin in patients with CV disease, “but have fewer side effects and better compliance,” Myeong-Ki Hong, MD, PhD, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea, told theheart.org/Medscape Cardiology.

Hong is senior author on the current observational study based on the CONNECT-DES registry, which compared rosuvastatin 10 mg/d plus ezetimibe 10 mg/d — used in RACING — with rosuvastatin 20 mg/d in a nationwide cohort of 72,050 patients.

“As we know, populations who are enrolled in randomized studies do not sufficiently represent real patients in practice,” he observed, “so we wanted to evaluate the generalizability of the RACING results in daily clinical practice.”

Deepak L. Bhatt, MD, said he likes studies that look at whether clinical trial results “play out in the real world,” as this one did. “They have largely replicated the results of the RACING trial,” suggesting the approach using a moderate-intensity statin “is the way to go,” Bhatt, Mount Sinai Health System, New York City, who was not affiliated with the current report, told theheart.org/Medscape Cardiology. “In fact, the moderate-intensity combination regimen was actually better in this study.”

He said the observed reduction in new-onset diabetes with the moderate-intensity statin approach is also important. “There is a link between high-dose statins and diabetes. So, if given the choice, if you can get the benefits from a cardiovascular perspective with a lower risk of diabetes, it makes sense to use the combination therapy.”

Bhatt said he had been using high-intensity statin monotherapy in his high-risk patients, but RACING made him reconsider the value of moderate-dose statin combination therapy. “Going with lower doses of two drugs instead of high doses of one drug minimizes side effects and, in some cases, can even enhance efficacy — so this is not an unreasonable paradigm.”

In the current cohort study of patients prescribed rosuvastatin after DES implantation, 10,794 received rosuvastatin 10 mg/d plus ezetimibe 10 mg/d, and 61,256 were put on rosuvastatin 20 mg/d.

Hazard ratio (HR) risk reductions with the dual-agent lipid-lowering therapy approach, compared with high-intensity statin monotherapy, were more favorable for the primary composite clinical endpoint and important secondary events:

• HR, 0.75 (95% CI, 0.70 – 0.79; P < .001) for CV death, MI, coronary artery revascularization, HF, or stroke at 3 years

• HR, 0.85 (95% CI, 0.78 – 0.94; P = .001) for statin discontinuation

• HR, 0.80 (95% CI, 0.72 – 0.88; P < .001) for new-onset diabetes requiring medication

But HRs for rhabdomyolysis, cholecystectomy, or a new cancer diagnosis did not indicate significant differences between the two groups.

“Now that there is evidence to support the favorable clinical outcomes of combination lipid-lowering therapy with moderate-intensity statin plus ezetimibe” for secondary prevention from both RACING and a study reflecting daily clinical practice, Hong said, “physicians may feel more comfortable with this approach.”

The registry analysis “is remarkable not only for validating the results of the RACING trial in routine clinical practice in a high-risk secondary prevention population, but also for its innovative methodology,” states an accompanying editorial by Ori Ben-Yehuda, MD, Sulpizio Cardiovascular Center, University of California-San Diego, La Jolla.

Use of such a large single-payer database in their study “affords even greater external validity to the findings, complementing the internal validity of the randomized RACING trial,” Ben-Yehuda writes.

The rationale for combination therapy is strong, but additional data would be helpful, particularly for informing guidelines, he continues. “A pragmatic trial randomizing a broad racial and ethnic group of patients to low-dose statin,” such as a starting dose of 10 mg/d atorvastatin or 5 mg/d rosuvastatin “plus ezetimibe vs high-intensity statin alone would provide much needed data to help guide lipid-lowering therapy for millions of patients and hopefully increase persistence on therapy.”

The study was supported by the Cardiovascular Research Center, Seoul, South Korea. Hong and Ben-Yehuda have disclosed no relevant financial relationships. Bhatt has previously disclosed grants and/or personal fees from many companies; personal fees from WebMD and other publications or organizations; and having other relationships with Medscape Cardiology and other publications or organizations.

J Am Coll Cardiol. 2023;82(5):401-410, 411-413. Full text, Editorial

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