Lower Cholesterol Cuts CV Events: Treat Stroke to Target Trial

PHILADELPHIA, PA—Prescribing statins to achieve a more aggressive LDL treatment target in patients who have had a TIA or ischemic stroke of atherosclerotic origins reduces the risk of major cardiovascular events, results from the Treat Stroke to Target trial show.

The study, which was stopped prematurely due to a funding shortfall, should help fill an evidence gap in stroke, where the best target for LDL cholesterol-lowering is unknown, said Pierre Amarenco, MD (Paris University, France). Amarenco presented the trial results here today at the American Heart Association 2019 Scientific Sessions. The study was published simultaneously in the New England Journal of Medicine.

“In our trial involving patients with an ischemic stroke or TIA and with evidence of atherosclerotic disease, those who were assigned to a target LDL cholesterol level of less than 70 mg/dL with the use of statins and, if required, ezetimibe, had a lower risk of a composite endpoint of major cardiovascular events than those who were assigned to a target range of 90 mg to 110 mg/dL,” Amarenco and colleagues write.

Guidelines already recommend high-intensity statins for patients with prior stroke, based primarily on the results of the SPARCL study, but whether aggressive reductions in LDL levels yield more benefit than a more-moderate target is unknown.

Lowering LDL Cholesterol in Stroke

The Treat Stroke to Target trial was conducted at 77 sites in Korea and France, with a planned enrollment of 3,786 patients. Recruitment was slow, however, such that by the time the steering committee stopped the trial, only 2,873 patients taking statins, ezetimibe, or both, had been randomized to the lower target of target of either 70 mg/dL or the higher target of 90-110 mg/dL.

At baseline, the median LDL for the entire cohort was 135 mg/dL; by the end of follow-up at 3.5 years, patients randomized to the more-aggressive target had reached a mean LDL level of 65 mg/dL, while the comparator group reached a mean of 95 mg/dL.

At follow-up, the primary composite outcome of ischemic stroke, MI, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes, had occurred in 8.5% of patients in the lower-target group and in 10.9% of patients with the more moderate LDL goal, a 22% relative risk reduction (HR 0.78; 95% CI 0.61-0.98). Importantly, the incidence of intracranial hemorrhage (ICH)—a key concern for aggressive LDL-lowering in these patients—was not increased in patients in the lower-target group. Nor were there any differences in the rates of new diabetes, an acknowledged risk of statin therapy.

Interpretation of the trial’s underpowered secondary endpoints is difficult, given the trial’s early termination, Amarenco noted during a morning press conference. As such, “the results should be taken with caution. But if you look at the entire context of lipid-lowering trials, this reduction that we observed with the lower target group was really in line with the regression line, speaking [to] the lower LDL, the better, and also speaks to the fact that LDL cholesterol is casually related to atherosclerosis.”

Press conference moderator, Donald Lloyd-Jones, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), agreed, pointing out that the 22% relative risk reduction seen in this trial is “right on what we would have expected from the very large composite data from the Cholesterol Treatment Trialists, focused on statin therapy.”

We continue to see the general theme of lower LDL is better, and statins are certainly a good safe way to get people lower. Donald Lloyd-Jones

He continued: “This is a slightly different patient population . . . than our garden-variety coronary patients, and I think the concern about ICH continues to be something that we wonder a little bit about—should we be driving our stroke patients as low as we try to get our coronary patients? I think these data will certainly help us, but we continue to see the general theme of lower LDL is better, and statins are certainly a good safe way to get people lower, but we may have some more conversations about that with our stroke patients than we do in our coronary patients.

Also chiming in, AHA president-elect Mitchell Elkind, MD (Columbia University, New York, NY), who was also the discussant in the subsequent main-tent presentation of the trial, pointed out that despite enrolling fewer than hoped for subjects, the trial still demonstrated a statistically significant reduction in the primary endpoint. “It’s true there was less data about the other secondary outcomes, but the proof is in the pudding to some extent,” he said.

Asked whether these kinds of trial results might inspire a return to targets in cholesterol guidelines—LDL cholesterol targets were controversially abandoned in the 2013 US guidance, and not reinstated in 2018—Lloyd-Jones joked that he’d been wondering whether he’d be asked this question. Lloyd-Jones was lead author on the risk assessment paper that accompanied the 2018 document. The Treat Stroke to Target trial alone, he said, would not “flip us back” to a target-based approach to LDL cholesterol-lowering, he said, 

“I think actually the results of this study fit pretty nicely into the rubric of the 2018 cholesterol guidelines. [Those] said that our primary focus is getting the LDL cholesterol down by at least 50% in these high-risk secondary prevention patients, and we used the world ‘threshold’ rather than ‘target.’ So if the LDL remained above 70 mg/dL in a patient like [those] in this trial, that would be a reason to consider further therapy, either intensification of statins . . . or the addition of ezetimibe to get that patient lower.”

In some patients, he added, the “marginal gain starts to get smaller and smaller, and the costs of the medications that we might use to drive these patients [lower] are certainly still substantial.”

Also speaking to this point, Jennifer Robinson, MD (University of Iowa, Iowa City), who noted she was vice chair for the “much-maligned 2013 guidelines,” stressed that the focus back then has been on the intensification of statin therapy, which is quite safe. “I think as we get these other studies, it suggests what to do after you’ve maximized statin therapy,” she said. “And the nice thing is that it’s in an evidence-based way, it’s not just speculation. We know both the benefits and the harms of doing that.”