Treat to Target or With Intensity? Both Statin Tactics Cut MACE: LODESTAR

NEW ORLEANS, LA—Ever since statin guidelines were revised to urge physicians to prescribe high-intensity statins rather than treating to a specific LDL target, the debate has continued: is the “fire and forget it” approach really any better (or worse) than getting LDL cholesterol down to a specific threshold?  

The answer, according to the LODESTAR trial, is that a treat-to-target approach is noninferior to the guideline-recommended high-intensity strategy when it came to reducing the risk of major adverse cardiovascular events.

“To our knowledge, this study is the first randomized trial comparing 3-year clinical outcomes of a treat-to-target strategy with a target LDL-cholesterol level between 50 and 70 mg/dL versus a high-intensity statin strategy . . . in patients with coronary artery disease,” said lead investigator Myeong-Ki Hong, MD, PhD (Yonsei University College of Medicine, Seoul, Korea), who presented the findings during a featured clinical research session last week at the American College of Cardiology/World Congress of Cardiology (ACC/WCC) 2023. “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.

The study was simultaneously published in JAMA.

Prior US cholesterol guidelines, back in 2001, recommended physicians treat to a specific LDL target depending on the patient’s baseline risk, typically below 70 mg/dL in high-risk patients with atherosclerotic cardiovascular disease (ASCVD). In 2013, however, the US moved away from that approach and recommended physicians simply prescribe either a moderate- or high-intensity statin, depending on the patient’s risk. In ASCVD patients, physicians are advised to start a high-intensity statin (or the maximally tolerated dose) with the goal of reducing LDL-cholesterol levels by 50% or more.

The shift away from the treat-to-target strategy was controversial a decade ago and remains so today. Just last month, National Lipid Association (NLA) and American Society of Preventive Cardiology (ASPC) issued a statement urging the reintroduction of LDL measurements as a performance metric, rather than blindly prescribing high-intensity statins without gauging their efficacy.

As Hong and colleagues point out, the current approach—treat with a high-intensity statin—is simpler because it avoids adjusting statin therapy in follow-up based on LDL levels, but it raises concerns about individual response to treatment.  

“An alternative approach is to begin with moderate-intensity statins and titrate to a specific LDL cholesterol goal,” they write in their published paper. “This treat-to-target strategy could allow a tailored approach and facilitate patient-physician communication, which can enhance adherence to therapy. However, that strategy has not been well evaluated in randomized clinical trials and thus lacks sufficient evidence.”

Guiding Light From LODESTAR

Hong and colleagues randomized 4,400 patients (mean age 65 years; 28% female) to a target LDL cholesterol between 50 and 70 mg/dL or to treatment with a high-intensity statin without a specific LDL cholesterol level goal.

At baseline, the LODESTAR groups were well matched, with LDL-cholesterol levels of 86.5 mg/dL. Among the treat-to-target group, 17% had their medication dose up-titrated, 9% had the dose down-titrated, and 73% were maintained on their current statin because their LDL levels were in the optimal zone. Overall, 92% of the high-intensity statin group received a high-intensity statin, while 54% in the treat-to-target arm required a high-intensity statin.

In terms of LDL-lowering, 55.7% of the treat-to-target group had an LDL-cholesterol level less than 70 mg/dL at 6 weeks compared with 61.6% of those in the high-intensity group (P < 0.001). Over time, the gap closed so that by 3 years there was no significant difference in the percentage of patients with LDL levels less than 70 mg/dL: 58.2% in the treat-to-target versus 59.7% in the high-intensity arm, respectively (P = 0.41).

At 3 years, the primary endpoint of all-cause mortality, MI, stroke, or coronary revascularization did not differ between the two strategies, occurring in 8.1% in the treat-to-target and 8.7% in the high-intensity strategies, respectively (P < 0.001 for noninferiority). There were no significant differences in any of individual components of the primary endpoint. Safety was similar between the groups, although new-onset diabetes was numerically lower in the treat-to-target group (5.6% vs 7.0%; P = 0.07).

In terms of why so few patients in the treat-to-target arm had LDL levels in the less-than-70 mg/dL zone, Hong believes it might be explained by the relative lack of combination therapy in LODESTAR. The study protocol specifically didn’t advise clinicians to add ezetimibe because investigators were focused on the two statin strategies. Additionally, combination therapy was emphasized more in the 2018 US guidelines, but less so when this trial was initiated in 2016. Additionally, patients might have been reluctant to add another drug to their high-intensity statin regimen, say investigators.

What About Even Lower LDL Levels?

Eugene Yang, MD (University of Washington, Bellevue), one of the discussants during the ACC/WCC 2023 session, said there was some hint of benefit with the treat-to-target approach, and that he wondered if longer follow-up might have translated into a clinical benefit.

“From my perspective, when you look at a study like this, even though it’s one study, open label, [you ask]: do you think this will have clinical implications?” said Yang. In certain clinics, where physicians might see a lot of patients in a single day, prescribing a high-intensity statin makes it easier, noting they simply have to monitor liver function and other side effects on occasion, said Yang.

However, he pointed out there is evidence supporting even lower LDL-cholesterol levels in high-risk patients, such as those with ASCVD. In fact, in Europe, where successive guideline documents had retained LDL targets, the most recent guidelines, took this one step further, recommending that physicians treat high-risk patients with ASCVD to a target of less than 55 mg/dL. It’s unknown if that more-aggressive goal might yield a benefit over simply prescribing a high-intensity statin, said Yang.

Hong said patients can be nervous about starting statin therapy, particularly at high doses. There are concerns about statin-associated muscle symptoms or the potential risk of diabetes mellitus. The treat-to-target strategy, he said, allows physicians to start with moderate-intensity statin, upping the dose only as needed.