Switch to Rosuvastatin Plus Ezetimibe From Statin Monotherapy to Achieve Target LDL-Cholesterol Goal: A Multi-Center, Open-Label, Single-Arm Trial

Article information

J Stroke. 2025;27(2):275-278

Publication date (electronic) : 2025 May 31

doi : https://doi.org/10.5853/jos.2024.05015

Hong-Kyun Park¹, Jong-Ho Park², Hee-Kwon Park³, Kyusik Kang⁴, Keun-Hwa Jung⁵, Beom Joon Kim⁶, Jin-Man Jung⁷, Young Seo Kim⁸, Yong-Seok Lee⁹, Hyo Suk Nam¹⁰, Yeonju Yu¹¹, Juneyoung Lee¹¹, Keun-Sik Hong^,1

¹Department of Neurology, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea

²Department of Neurology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea

³Department of Neurology, Inha University Hospital, Inha University School of Medicine, Incheon, Korea

⁴Department of Neurology, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea

⁵Department of Neurology, Seoul National University Hospital, Seoul, Korea

⁶Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Korea

⁷Department of Neurology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea

⁸Department of Neurology, Hanyang University Seoul Hospital, Hanyang University College of Medicine, Seoul, Korea

⁹Department of Neurology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea

¹⁰Department of Neurology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

¹¹Department of Biostatistics, Korea University College of Medicine, Seoul, Korea

Correspondence: Keun-Sik Hong Department of Neurology, Inje University Ilsan Paik Hospital, 170 Juhwa-ro, Ilsanseo-gu, Goyang 10380, Korea Tel: +82-31-910-7680 E-mail: nrhks455@gmail.com

Received 2024 November 20; Revised 2024 December 24; Accepted 2025 February 25.

Dear Sir:

For patients with cerebrovascular disease of atherosclerotic origin, the target low-density lipoprotein cholesterol (LDL-C) level is less than 70 mg/dL [1]. However, despite being on statin monotherapy, approximately 50% of patients fail to achieve the target LDL-C goal [2,3]. Further LDL-C reduction by increasing statin dosage is limited; doubling the statin dose generally results in only a 5% to 7% absolute reduction. Recent clinical trials involving patients with atherosclerotic cardiovascular disease or recent stroke demonstrated the superiority of the rosuvastatin/ezetimibe combination therapy over doubling rosuvastatin dose for LDL-C reduction [4,5]. However, there is no salient data on achieving target LDL-C goals by adding ezetimibe in Korean patients with ischemic stroke, transient ischemic attack (TIA), or cerebral atherosclerosis who were indicated for and have been on statin monotherapy. Switch to ROSuvastatin plus Ezetimibe Treatment from statin monotherapy for Target LDL-C goal Achievement in patients with ischemic STROKE, TIA, or cerebral atherosclerosis (SROSETTA-Stroke) aimed to evaluate the effectiveness of switching to combination of ezetimibe and rosuvastatin with equivalent prior statin intensity on achieving LDL-C <70 mg/dL in patients with ischemic stroke, TIA, or cerebrovascular atherosclerosis whose LDL-C was ≥70 mg/dL despite statin monotherapy.

This was an investigator-initiated, multicenter, open-label, single-arm trial conducted in 10 centers in South Korea. The trial was supported by Samjin Pharm, which provided study medications but had no role in the trial’s design, conduct, data collection, analysis, interpretation of data, or preparation of the manuscript. All data were collected by site investigators and monitored by an independent research organization contracted by the principal investigator’s academic institution. The trial was registered at cris.nih.go.kr (KCT0008455).

Key inclusion criteria were (1) ischemic stroke, TIA, or cerebral atherosclerosis without clinical cerebral ischemia, (2) statin monotherapy before enrollment, and (3) baseline LDL-C level >70 mg/dL. Detailed inclusion and exclusion criteria are described in the Supplementary Table 1. The local institutional review boards of all participating centers approved the study. Enrolled patients or their legally authorized representatives provided written informed consent.

Following screening, baseline LDL-C and patient characteristics were recorded, and study medication was selected based on the equivalent dose of prior statin intensity (Supplementary Table 2). During the study period, we assessed adherence and adverse events. Final LDL-C levels were measured at day 90±30.

The primary endpoint was the proportion of patients achieving an LDL-C level <70 mg/dL at 90 days. Secondary endpoints included relative and absolute LDL-C reduction, LDL-C level <55 mg/dL, multiple lipid goals achievement (total cholesterol <200 mg/dL, LDL-C <70 mg/dL, and triglyceride <150 mg/dL), major cardiovascular events (including stroke, acute coronary syndrome, revascularization, or vascular death), all cause of death, and new-onset diabetes.

The sample size was calculated by assuming the primary endpoint rate of 60% with a 95% confidence interval (CI) of 55%– 65% at a significance level of 0.05, based on the findings of ROSETTA- Stroke, which enrolled statin-naïve Korean patients with acute ischemic stroke [5]. Accounting for a 10% dropout rate, the planned sample size was 410. Efficacy endpoints were analyzed using the modified intention-to-treat (mITT) population, which included patients who took at least one dose of the study medications and completed LDL-C measurements at 90 days. Per-protocol analysis included patients who had no major protocol violation, took more than 80% of the study medications, and did not take non-study lipid-lowering agents. The safety population comprised patients who were enrolled and took at least one dose of study medication.

Between July 23, 2023, and August 24, 2024, 410 patients were enrolled; 397 patients were included in the safety population, 381 in the mITT population, and 340 in the per-protocol (PP) population (Supplementary Figure 1). Table 1 presents detailed baseline characteristics. The mean age was 66.4 years, and 35.4% were female. Prior to enrollment, atorvastatin (60%) and rosuvastatin (30%) were the predominant statins used, with varying intensities: low (40%), moderate (37%), and high (23%). The mean baseline LDL-C level was 94.5 mg/dL.

Table 1.

Baseline characteristics of the study population (mITT population)

The study met the primary endpoint, with 74.3% of patients achieving LDL-C levels <70 mg/dL at 90 days. Secondary outcomes showed a 33.1% relative LDL-C reduction, a 32.3 mg/dL absolute LDL-C reduction, with 41.2% of patients reaching <55 mg/dL and 63% meeting multiple lipid goals. One major vascular event occurred (recurrent ischemic stroke), with no deaths or new diabetes cases reported (Table 2). The results of the PP population analyses were consistent with those of the mITT population analyses (Supplementary Tables 3 and 4). In subgroup analyses, males, patients aged ≥70 years, those with prior moderate or high-intensity statin use, and those with baseline LDL-C <100 mg/dL were more likely to achieve the target LDL-C goal (Supplementary Figure 2).

Table 2.

Study outcomes (mITT population, n=381)

In terms of safety, 13.4% of patients experienced any adverse events, and 2% had treatment-emergent adverse events (TEAEs). There were no cases of rhabdomyolysis, and only 0.8% had significant liver enzyme elevation. There was 1 case of serious TEAE of acute pancreatitis, which was resolved after stopping the study medication (Table 3).

Table 3.

Adverse events (safety population)

This trial showed that switching to ezetimibe plus rosuvastatin of equivalent intensity to prior statins resulted in a substantial LDL-C reduction. Three-quarters of patients achieved the target LDL-C goal of <70 mg/dL. In addition, 41.2% had LDL-C <55 mg/dL, the relative LDL-C reduction was 33.1%, and the absolute LDL-C reduction was 32.3 mg/dL, along with 63% of multiple lipid goal achievement rate. Given the 2% of TEAE and only one reversible serious TEAE, the safety of this switching strategy looks acceptable.

Our findings align with previous studies on the efficacy of combining ezetimibe with statins for LDL-C reduction. In a prior meta-analysis, the relative reduction with adding ezetimibe to ongoing statins was 26.0% [6]. The relative LDL-C reduction of 33.1% observed in this trial looks greater. For clinical efficacy with LDL-C reduction, prior meta-analyses indicated that 39 mg/dL decrease in the achieved LDL-C level was associated with a stroke risk reduction of 21.1%–23.5% [7,8]. When applying the result of S-ROSETTA-Stroke trial to the existing data, the absolute LDL-C reduction of 32.3 mg/dL in this trial would be expected to result in around 20% reduction in future stroke risk by adding ezetimibe.

This study has several limitations as follows. The primary endpoint was the LDL-C level rather than clinical outcomes. The short follow-up period restricts the ability to assess long-term efficacy and safety, potentially underestimating treatment effects or failing to detect delayed adverse events. The open-label design may be liable to reporting bias for clinical endpoints. Finally, the exclusive enrollment of Korean patients limits the generalizability of the results to other populations.

In conclusion, switching to ezetimibe plus rosuvastatin with equivalent prior statin intensity resulted in a substantial LDL-C lowering reduction with favorable safety profiles in Korean patients with ischemic stroke, TIA, or cerebral atherosclerosis who are indicated for lipid-lowering therapy, suggesting this approach as an effective strategy for achieving the target LDL-C level when LDL-C lowering with statin monotherapy is insufficient.