A strategy of using moderate statin therapy and adjusting until a target low-density lipoprotein cholesterol (LDL-C) level of 50 to 70 mg/dL was achieved was noninferior to a high-intensity statin regimen at 3 years in patients with coronary artery disease (CAD), new randomized trial results show.
Myeong-Ki Hong, MD, of Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea, presented these findings during a Featured Clinical Research session Monday at the American College of Cardiology Scientific Sessions 2023 in New Orleans. A manuscript reporting these results was simultaneously published online in JAMA.
Some guidelines recommend that patients with CAD be started on high-intensity statins until LDL-C is reduced by at least half.
An alternative is to start these patients on moderate-intensity statins and adjust until they achieve a specific LDL-C goal. This so-called “treat-to-target” strategy, while allowing an approach tailored to the individual patient and possibly helping the patient adhere to the medication regimen, lacks evidence from randomized trials.
The LODESTAR Trial hypothesized the treat-to-target strategy, aiming at LDL-C levels between 50 and 70 mg/dL, would be noninferior to a high-intensity statin regimen with regard to 3-year clinical outcomes in patients with CAD.
The investigator-initiated, multicenter, open-label trial enrolled patients at 12 centers in South Korea from September 2016 through November 2019. A total of 4,400 patients were randomized, 2,200 each to the treat-to-target or high-intensity group. The moderate-intensity regimen consisted of 10 mg of rosuvastatin or 20 mg of atorvastatin daily, and the high-intensity regimen consisted of 20 mg of rosuvastatin or 40 mg of atorvastatin daily.
For patients in the treat-to-target group, moderate-intensity therapy was initiated for patients who were statin-naïve, and for those already taking statins, their regimen was maintained if their LDL-C was below 70 mg/dL or was up-titrated for higher LDL-C levels. At follow-up, treat-to-target patients with LDL-C higher than 70 mg/dL were up-titrated, those with LDL-C between 50 and 70 mg/dL were maintained, and those with LDL-C lower than 50 mg/dL were down-titrated.
The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), defined as a composite of all-cause mortality, myocardial infarction, stroke or any coronary revascularization, at 3 years.
At baseline, the patients’ mean age was 65.1 ± 9.9 years and 27.9% were female.
In the treat-to-target group, 43% received moderate-intensity statins and 54% received high-intensity dosing. The mean LDL-C level at 3 years was 69.1 ± 17.8 mg/dL in the treat-to-target group and 68.4 ± 20.1 mg/dL in the high-intensity group (p=0.21).
Most patients in the treat-to-target group (73%) were maintained on the statin regimen on which they began the study. Of the remainder, 17% were up-titrated and 9% were down-titrated at some point during the 3-year trial period.
The primary endpoint rates were similar between the groups (treat-to-target 8.1% vs. high-intensity 8.7%; absolute difference: -0.6 percentage points, upper boundary of the one-sided 97.5% confidence interval, 1.1 percentage points; p<0.001 for noninferiority).
There was also no significant difference between the groups in rates of all-cause mortality (2.5% vs. 2.5%, p=0.99), myocardial infarction (1.6% vs. 1.2%; p=0.23) and stroke (0.8% vs. 1.3%; p=0.13).
The only secondary endpoint that did show a difference was a post hoc secondary outcome, a composite of new-onset diabetes, amino-transferase or creatine kinase elevation, or end-stage kidney disease, which was significantly lower in the treat-to-target group (6.1% vs. 8.2%; p=0.009).
Subgroup analyses showed no differences between the treat-to-target or high-intensity statin strategy by age (younger or older than 65 years), sex, body mass index (above or below 25 kg/m2), baseline LDL cholesterol (above or below 100 mg/dL) or other characteristics.
Study limitations included that the trial was open-label, but an independent committee blinded to therapy assignment adjudicated all clinical events and assessed clinical endpoints. Lower event rates than anticipated were seen in the trial, which might have resulted in an underpowering of the noninferiority margin of 3.0 percentage points. Also, the trial recruited only patients with CAD, meaning a comparison of the treatment method in these patients compared with other types of patients might be needed. And only 60% of the treat-to-target group reached an LDL-C level below 70 mg/dL, which the investigators said might mean that other, non-statin therapies should be considered for patients who cannot achieve sufficient LDL-C levels with statin monotherapy.
“The treat-to-target strategy was noninferior to the high-intensity statin strategy in terms of a 3-year composite of all-cause death, myocardial infarction, stroke, or any coronary revascularization,” Hong concluded, adding that LODESTAR was, to the investigators’ knowledge, the first randomized trial to make this comparison in patients with CAD.
The trial received research grants from Samjin Pharmaceutical and Chong Kun Dang Pharmaceutical and was supported by the Cardiovascular Research Center in Seoul.