By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: A randomized, multicenter study of high-intensity statin therapy to a treat-to-target approach in coronary artery disease patients showed no difference in three-year outcomes. These results suggest treating to a target may be more suitable to individual patients compared to blanket high-intensity statin use.
SOURCE: Hong SJ, Lee YJ, Lee SJ, et al. Treat-to-target of high intensity statin in patients with coronary artery disease. A randomized clinical trial. JAMA 2023;329:1078-1087.
In patients with coronary artery disease (CAD), some guidelines recommend maximally tolerated statin therapy without a specific LDL cholesterol goal.1 Considering the safety concerns of such, Hong et al hypothesized high-intensity (HI) statins would be used less in a treat-to-target (TT) LDL strategy.
The authors performed a multicenter, randomized, open-label, noninferiority trial that included CAD patients at 12 centers in South Korea. They compared TT statin use to HI statin use. Patients were stratified at each center by baseline LDL levels (higher than 100 mg/dL), acute coronary syndrome (ACS), or diabetes. Also, patients in both groups were randomized to receive rosuvastatin or atorvastatin. Patients in the TT group started rosuvastatin 10 mg/day or atorvastatin 20 mg/day, then titrated to reach an LDL goal of 50 mg/dL to 70 mg/dL. In the HI group, the authors gave rosuvastatin 20 mg per day or atorvastatin 40 mg per day without regard to LDL levels. Using ezetimibe or other drugs to lower cholesterol was discouraged but not prohibited.
The primary endpoint was major cardiovascular (CV) or cerebral events at three years. Death was divided into CV and non-CV. A variety of secondary endpoints concerning non-major CV events and adverse drug effects also were evaluated. All patients who adhered to their assigned group’s treatment were included in the primary analysis. The authors also conducted clinically relevant subgroup analyses.
Between 2016 and 2019, investigators randomized 4,400 patients: mean age = 65 years; about 70% were men. During the three-year follow-up, mean LDL was 69 mg/dL in the TT group and 68 mg/dL in the HI group (P = 0.21). In the TT group, 58% achieved an LDL between 50 mg/dL and 70 mg/dL at three years, which was similar to the HI group. The primary endpoint occurred in 8.1% of the TT group and 8.7% of the HI group (P < 0.001 for noninferiority). None of the prespecified secondary endpoints differed between the groups, nor was there any difference in outcomes in any subgroup. The authors concluded the lack of a significant difference in outcomes between the two groups provides evidence suggesting a TT strategy may allow a tailored approach to statin therapy that is more acceptable to individual CAD patients.
COMMENTARY
This is a timely and important study, given the lack of agreement on these two techniques for cholesterol-lowering therapy for secondary prevention. Current practice at my institution is to start 80 mg/day of atorvastatin on everyone admitted for CAD. This approach is predicated on maximizing the touted beneficial pleiotropic effects of statins and presumed maximum LDL-lowering at this dose of a high-intensity statin. Once the patient is an outpatient, the dose rarely changes. At this dose, many patients become concerned they are going to experience adverse effects, and may discontinue therapy.
Although there was no significant difference in adverse effects between the two groups in the Hong et al study, there were marginally significant differences favoring the TT approach. New diabetes occurred in 5.6% of the TT group and 7% of the HI group (P = 0.07). New end-stage kidney disease was less common in the TT group (0.1% vs. 0.5% in the HI group; P = 0.05) and fewer TT patients discontinued statin therapy (1.5% vs. 2.2% in the HI group; P = 0.09). Thus, the authors believe their data support the TT approach, which would allow for lower doses (and perhaps less-potent) statins if LDL levels were at target. This also raises the issue of adding other drugs to lower LDL levels. Although the authors discouraged using ezetimibe, at three years follow-up 20% of the TT group vs. 11% of the HI group were on ezetimibe. Perhaps the failure to prescribe more LDL-lowering drugs explains the relatively small number of patients who achieved an LDL cholesterol level lower than 70 mg/dL.
Consider some limitations to the Hong et al study. For example, since this study ended, European guidelines have been revised to recommend achieving an LDL level lower than 55 mg/dL for secondary prevention.2 The Hong et al study was an open-label investigation, but an independent committee adjudicated all endpoints.
Since there were fewer events than the investigators predicted, this study may have been underpowered to show differences in outcomes. Part of the reason for the lack of events may have been that 74% of their population had been diagnosed with their qualifying CAD event more than a year before study entry. Finally, three years is a relatively short timeline for a secondary prevention study.
The Hong et al study buoys the concept that we need more and better drugs to lower LDL cholesterol. Although PCSK9 inhibitors were available during the study period, apparently none of the patients were taking them. Current PCSK9 agents require a subcutaneous injection, but oral agents are under investigation, as are other drugs that affect this metabolic pathway, such as bempedoic acid. In the future, statins may be just part of a multidrug approach to lowering LDL cholesterol, much as current hypertension therapy.
REFERENCES
1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e1082-e1143.
2. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-188.
A randomized, multicenter study of high-intensity statin therapy to a treat-to-target approach in coronary artery disease patients showed no difference in three-year outcomes. These results suggest treating to a target may be more suitable to individual patients compared to blanket high-intensity statin use.
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