- Appropriate lipid management is of critical importance in preventing further cardiac events in patients with atherosclerotic cardiovascular disease, yet different approaches exist to achieving lipid control
- In this study, investigators sought to assess whether a treat-to-target LDL strategy is noninferior to a strategy of high-intensity statins for long-term clinical outcomes in patients with coronary artery disease
- A targeted approach to reducing LDL-C was noninferior to the high-intensity statin strategy in terms of a 3-year composite outcome of all-cause death, myocardial infarction, stroke, or any coronary revascularization.
Statins are known to reduce cardiovascular events and make up the backbone of secondary prevention lipid management. The use of routine high-intensity statins for this indication is supported by an extensive body of evidence showing significant benefits across all levels of baseline LDL-C without a particular threshold. Targeting a specific LDL-C target, however, offers providers a different approach to lipid management that can accommodate for patient preference and side effects, yet has not been fully adopted by all guideline committees. Clear data is lacking comparing these two methods of secondary prevention with respect to all-cause death, myocardial infarction, stroke, or any coronary revascularization. In the study titled, Comparison Between Targeted Low-Density Lipoprotein Cholesterol Level Based Versus High-Intensity Statin Therapy In Patients With Coronary Artery Disease, or the LODESTAR trial, investigators sought to compare the incidence of the composite outcome of all-cause death, myocardial infarction, stroke, or any coronary revascularization between both approaches to lipid control.
The LODESTAR study was a randomized, open-label, noninferiority, multicenter trial at 12 centers in Korea. Patients with clinically diagnosed CAD, including stable ischemic heart disease or acute coronary syndrome (unstable angina, acute myocardial infarction), were enrolled. Reasonably, those unable to tolerate statins (hypersensitivity, allergy, severe adverse events) were excluded from the study along with those who had risk factors for myopathy with hereditary muscle disorder, hypothyroidism, alcohol use disorder, severe hepatic dysfunction (3 times normal reference values) or rhabdomyolysis. Additionally, those with life expectancy < 3 years or pregnant women (or women with potential childbearing), were also excluded. Patients were randomly assigned to receive either the LDL-C target strategy, with an LDL-C level between 50 and 70mg/dL as the target, or high-intensity statin treatment, which consisted of rosuvastatin, 20mg, or atorvastatin, 40mg.
The primary endpoint was a composite of all-cause death, myocardial infarction, stroke, or any coronary revascularization at 3 years, with a noninferiority margin of 3.0 percentage points. A total of 4400 patients were randomized to lipid management with either the fixed high-intensity statin therapy (n = 2200) or targeted LDL-C (n = 220). Additionally, patients in each group were randomized to rosuvastatin or atorvastatin. The primary outcome was the incidence of composite all-cause death, myocardial infarction, stroke, or any coronary revascularization over three years. The groups were well-matched with no statistical difference in measured patient characteristics or demographics. The mean (SD) LDL-C level for 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 statin group (n = 2200) (p = .21, compared with the treat-to-target group).
The primary end point occurred in 177 patients (8.1%) in the treat-to-target group and 190 patients (8.7%) in the high-intensity statin group (absolute difference, –0.6 percentage points [upper boundary of the 1-sided 97.5%CI, 1.1 percentage points]; P < .001 for noninferiority). There was no significant difference in the primary endpoint between the two lipid management approaches over a period of three years, 8.1% in the treat-to-target group and 8.7% in the high-intensity statin group (absolute difference, –0.6 percentage points [upper boundary of the 1-sided 97.5%CI, 1.1 percentage points]; P < .001 for noninferiority). More specifically, there was an absolute difference of 0.6% (high-intensity statin strategy 8.7%, treat-to-target strategy 8.1%) in the cumulative incidence which was not statistically significant. The p-value for non-inferiority was reached at < 0.001. Interestingly, there was a numerical trend towards benefit without statistical significance in secondary endpoints including new-onset diabetes, end-stage kidney disease, development of composite lab abnormalities (aminotransferase elevation, creatine kinase elevation, creatine elevation); numerically, but without statistical significance more patients in the high-intensity statin strategy discontinued statin therapy. Subgroup analyses for the primary endpoint did not reveal statistically significant differences, but a general trend towards benefit in the treat-to-target group with regard to age, sex, BMI, diabetes, HTN, and baseline LDL cholesterol.
The study concluded that a targeted approach to lipid management was noninferior to the high-intensity statin strategy over the three-year study period. Dr. Myeong-Ki Hong suggested that the treat-to-target approach could offer providers a sense of patient-centered flexibility when considering those who experience side effects from statins who are at target LDL-C levels with a high-intensity statin. It will be interesting to see how these data will inform future guidelines, especially with potential future studies increasing the number of participants, longer follow up times, and applying new therapies to bring LDL-C target levels lower.