Treat-to-Target or High-Intensity Statin in Clinical CAD?

How secondary prevention statins are given to push LDL cholesterol levels lower, whether in a high-intensity statin regimen or by dosage titration to meet LDL targets, may make little difference to clinical outcomes, suggests a randomized trial.

The latter “treat-to-target” strategy was noninferior to the high-intensity statin approach for death or cardiovascular events at 3 years in patients with clinical coronary disease in the 4400-patient LODESTAR trial, conducted at 12 centers in South Korea.

That means treating-to-target can be an effective alternative to a blanket high-intensity statin approach that, although consistent with US guidelines, may confer a greater statin load than some patients need to reduce LDL-C levels sufficiently, say researchers.

The target-based strategy, though “less convenient” and possibly more costly than the alternative, may be preferred by some patients concerned about the drugs’ potential for side effects, especially muscle symptoms, proposed Myeong-Ki Hong, MD, PhD.

Patients treated-to-target in LODESTAR usually started with a moderate-intensity statin, with assay-guided uptitration as needed to achieve LDL-C levels in the range of 50 to 70 mg/dL.

On such a regimen, some patients can hit their LDL-C target on only moderate-intensity statins, alleviating their concerns and perhaps improving their statin adherence, said Hong, of Severance Hospital and Yonsei University College of Medicine, Seoul, South Korea.

Hong presented LODESTAR March 6 at the American College of Cardiology (ACC) Scientific Session/World Congress of Cardiology (WCC) 2023, held live and virtually from New Orleans, Louisiana. He is also senior author on the study’s report published simultaneously in the Journal of the American Medical Association.

Why Treat to Target?

A one-size-fits-all, high-intensity statin approach avoids the bother and costs of statin titrated guided by serial LDL-C assays, but doesn’t consider “individual variability in drug responses,” Hong told | Medscape Cardiology in an email.

In contrast, he said, statin treatment to LDL-C target “could allow a tailored approach and facilitate patient–physician communication, which can enhance adherence to therapy,” potentially rendering high-intensity statins “less needed.”

Indeed, only 54% of treat-to-target patients in LODESTAR received high-intensity statins compared with 92% of those in the high-intensity statin arm, Hong reported.

The latter strategy is consistent with current US guidelines for secondary prevention, which recommend treatment to achieve at least a 50% drop in LDL-C using high-intensity statins plus, as necessary, non-statin LDL-lowering agents.

LODESTAR’s target-based approach called for lowering LDL-C levels to the 50-70 mg/dL range, in line with guidelines when the trial was designed in 2015, the report states.

Both approaches, Hong said, “are now widely accepted and used” in South Korea, with acknowledgment of their “advantages and disadvantages.” But they had not previously been directly compared for efficacy and safety in a randomized trial.

Treating Enough to Target?

“It’s not too surprising” that the LODESTAR treat-to-target approach was noninferior to the high-intensity statin strategy, Salim S. Virani, MD, PhD, of Baylor College of Medicine, Houston, Texas, told | Medscape Cardiology.”

If LDL-C levels are cut to a similar degree using the two approaches, as they were in the trial, “you would expect that the event reduction will be the same,” said Virani, who is also vice provost in the Office of Research and Graduate Studies at the Aga Khan University, Karachi, Pakistan, but not associated with LODESTAR.

Virani agrees that some patients who are statin “hyper-responders” may achieve their LDL-C targets on no more than a moderate-intensity statin, thereby avoiding escalation to high-intensity statins. In practice, however, most patients would either proceed to high-intensity statins, as tolerated, or add a non-statin LDL-lowering medication to get below 70 mg/dL.

But LODESTAR discouraged the addition of non-statin LDL-lowering therapy in the treat-to-target group, even when high-intensity statins weren’t enough. That was so the study could “focus on the strategy for choosing statin intensity and avoid confounding by any imbalance in their use,” the report states.

Partly as a result, perhaps, many of the patients in this trial failed to reach an LDL-C of 70 mg/dL or lower. About 40% of the treat-to-target group and fully one third of the high-intensity statin group were above goal at 3 months, the shortfalls persisting throughout the trial.

For practice, “I think this trial is perhaps not as relevant as one would want it to be,” Virani said. There are now four non-statin drug therapies “at our disposal to lower LDL-cholesterol levels even further.” They include long-established ezetimibe and more recently the PCSK9 inhibitors, the small interfering RNA inclisiran (Leqvio), and — as recently demonstrated in the CLEAR Outcomes trial — bempedoic acid (Nexletol). 

Similar LDL-C Reductions

LODESTAR entered 4400 patients at 12 centers in South Korea with clinically defined stable ischemic heart disease, unstable angina, or history of myocardial infarction (MI). About 28% were women.

They were randomly assigned in equal numbers to assay-guided treat-to-target statin therapy or to receive high-intensity statins, that is, rosuvastatin 20 mg or atorvastatin 40 mg.  

Mean LDL-C levels plunged to below 70 mg/dL in both groups by both 6 weeks and 3 months, although slightly but significantly further for the high-intensity statin group. The levels were not significantly different, however, from 3 months to the end of the 3-year follow-up. By then, mean LDL-C levels had reached 69.1 mg/dL in the treat-to-target group and 68.4 mg/dL in the high-intensity statin group (P = .21).

Levels of LDL-C 70 mg/dL or lower were achieved within 3 months by 59.2% in the treat-to-target group and 67.3% of patients in the high-intensity statin group (P = .02). With the two groups combined, that degree of LDL reduction was achieved 55.7%, 60.8%, and 58.2% of patients at 1, 2, and 3 years, respectively, with no significant differences between the groups.

The rate for the trial’s composite primary endpoint at 3 years was 8.1% for the treat-to-target group and 8.7% for those assigned to high-intensity statins (P < .001 for noninferiority). The endpoint included death, MI, stroke, or coronary revascularization. Rates for the different events making up the composite were not significantly different between the two groups.

In practice, Virani said, probably most patients would not gain much from the treat-to-target approach if its purpose is to allow lower-intensity statin therapy.

“In a patient who is willing to take high-intensity statin therapy, I don’t think it matters,” he said. In might be helpful, however, for “a very small subgroup of patients who may not want to take high-intensity statins and aren’t very interested in any of the non-statin therapy options.”

Such persons, he proposed, might include those with coronary disease, for example, who take a lot of pills every day. “It would be in the uncommon setting where the patient is extremely concerned about pill burden, or their copays, and they do not want another medication added.”

Hong discloses receiving consultant fees or honoraria from Medtronic; fees for speaking from Medtronic, Edward Lifesciences and Viatris Korea; research grants from Samjin Pharmaceutical and Chong Kun Dang Pharmaceutical; and other support from the Cardiovascular Research Center, Seoul, Korea. Disclosures for the other authors are in the report. V irani discloses research grant support from the US Department of Veterans Affairs, the National Institutes of Health, and the Tahir and Jooma Family; and honoraria from the American College of Cardiology.

American College of Cardiology Scientific Session/World Congress of Cardiology 2023, Session 411 – Featured Clinical Research III. 411-12 – Comparison Between Targeted Low-Density Lipoprotein Cholesterol Level Based Versus High-Intensity Statin Therapy In Patients With Coronary Artery Disease. Presented March 6, 2023.

JAMA. Published online March 6, 2023. Abstract

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