More patients with established atherosclerotic cardiovascular disease (ASCVD) achieved a low-density lipoprotein (LDL) cholesterol of less than 70 mg/dL, and fewer discontinued treatment with ezetimibe plus a moderate-dose statin, than did those on high-intensity statin monotherapy, a noninferiority trial shows.
While it’s now established that drug combinations can achieve better efficacy with lower risks than high-dose monotherapy, the study is the first to show the benefits of the strategy for ASCVD in a randomized trial with long-term follow-up.
The primary endpoint – 3-year composite of cardiovascular death, major cardiovascular events, or nonfatal stroke – occurred in about 9% of patients in each group, showing non-inferiority.
Furthermore, the authors suggest that ezetimibe combination therapy be considered earlier in the treatment of those at high risk of adverse events, rather than doubling the statin dose.
The study was published online in The Lancet.
Less intolerance, less discontinuations
The open-label study, dubbed RACING, randomized 3,780 patients with ASCVD to receive moderate-intensity rosuvastatin 10 mg plus ezetimibe 10 mg or high-intensity 20 mg rosuvastatin monotherapy. Participants’ average age was 64 and 75% were men.
The primary endpoint occurred in 9.1% of patients in the combination therapy group and 9.9% in the high-intensity monotherapy group. The absolute between-group difference was −0.78% (90% confidence interval [CI], −2.39 to 0.83), well below the 2% noninferiority margin.
In the combination therapy group, LDL cholesterol concentrations of less than 70 mg/dL were achieved in 73% of patients at 1 year, 75% at 2 years, and 72% at 3 years. By contrast, in the monotherapy group, the lower concentrations were seen in 55% at 1 year, 60% at 2 years, and 58% at 3 years.
Further, a post hoc analysis showed LDL concentrations of less than 55 mg/dL at 1, 2, and 3 years in 42%, 45%, and 42% of patients in the combination therapy group versus 25%, 29%, and 25% of those in the high-intensity statin monotherapy group.
Eighty-eight patients (4.8%) on combination therapy discontinued medication or received a dose reduction, versus 150 patients (8.2%) on monotherapy.
Rates of myonecrosis were similar in the combination therapy and high-intensity statin groups (11 vs. 13), whereas myalgia was more common with high-intensity statins (29 vs. 17). The open-label design could have led to bias in reporting of patient symptoms, the authors noted. All clinical events, however, were adjudicated by an independent committee masked to treatment assignment.
There might be “some level of difference” when extending the findings to other populations because the trial involved only Koreans, coauthor Myeong-Ki Hong, MD, Yonsei University, Seoul, South Korea, acknowledged in response to a query from this news organization. He thinks the findings can be applied broadly nonetheless, and his team is currently investigating whether certain patients might benefit more than others from the combination.
Various options for patients
“The field of hypertension changed [its] guidelines almost 20 years ago to consider the initial use of combination therapy in hard-to-treat patients,” Christie Mitchell Ballantyne, MD, Baylor College of Medicine, Houston, said in an interview. He coauthored an accompanying editorial with Baylor colleague Layla A. Abushamat, MD.
“We now have enough evidence of the efficacy and safety of combination therapy to consider early initiation of this approach in patients with challenging lipid disorders who are at increased risk of ASCVD events,” affirmed Dr. Ballantyne.
“This study reinforces important principles in the management and secondary prevention of cardiovascular disease, namely that LDL reduction and associated risk reduction can be achieved in various ways,” said Daniel Muñoz, MD, MPA, executive medical director of the Vanderbilt Heart & Vascular Institute, Vanderbilt University Medical Center, Nashville, Tenn.
However, he noted, “The high-intensity statin dose used as a comparator in this study was rosuvastatin 20 mg. In clinical practice, we often target maximally aggressive reduction of LDL via higher doses – that is, rosuvastatin 40 mg or atorvastatin 80 mg.”
The bottom line, said Dr. Muñoz, who was not involved in the study: “There are different ways to achieve LDL-lowering and associated risk reduction in patients with CVD. For patients who warrant but might not tolerate high-intensity statin therapy, this study supports the use of a moderate-intensity statin in combination with ezetimibe.”
The study was funded by Hanmi Pharmaceutical, Seoul, South Korea. One study coauthor received an institutional research grant from the company. No other authors reported relevant financial relationships, nor did Dr. Ballantyne, Dr. Abushamat, or Dr. Muñoz.
A version of this article first appeared on Medscape.com.