Which statin strategy is better?

Titrated individually according to LDL target value (“Treat to Target”) or uniformly high doses for all patients (“High Intensity”)? Which of the two strategies is clinically better in the case of lipid lowering with statins has been unclear. The two have now been directly compared for the first time in a randomized trial.

Patients with coronary artery disease (CAD) are considered to be at high or very high risk for future adverse cardiovascular events. For this patient population, intensive lowering of low-density lipoprotein cholesterol (LDL-C) levels by therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is recommended. Meta-analyses have shown an association between absolute reductions in LDL-C levels with statins and a proportional reduction in major vascular events [2–5]. Some guidelines recommend initial treatment with high-dose statins (“high-intensity” approach) for the treatment of LDL-C levels to achieve a reduction in LDL-C levels of at least 50% [2–6]. High-dose or maximum-tolerated intensity can be maintained without a target [2–6]. The use of high-intensity statins may be straightforward because it reduces the need to adjust statin intensity according to the progression of LDL-C levels, but it raises concerns about individual variability in drug response and adverse effects of long-term use of high-intensity statins [7]. An alternative approach is to start with moderate-intensity statins and titrate to a specific LDL-C target. This “treat-to-target” strategy allows for a tailored approach and can facilitate patient-physician communication [3,8–10].

South Korean investigators directly compared the two strategies for the first time in the randomized LODESTAR trial. The initial hypothesis was that the “treat-to-target” approach, with LDL-C levels between 50 and 70 mg/dL as the target, would be “non-inferior” to “high-intensity” statin therapy with 20 mg rosuvastatin or 40 mg atorvastatin, in clinical terms in CHD patients [1].

LDL value of 50 to 70 mg/dl as target value

A total of 4400 patients (mean age, 65 years; 28% women) with documented coronary disease were enrolled and assigned to two groups. In the treat-to-target group, the target LDL-C level was the lowest LDL-C level recommended for the population in the most recent guidelines at the time of study design (August 2015) [8,9,11], which was below 70 mg/dL. Statin intensity was titrated as follows: In patients not taking statins, moderate-strength statin therapy was initiated. In those already taking a statin, equivalent intensity was maintained if LDL-C was below 70 mg/dL at randomization. Intensity was up-titrated when LDL-C was 70 mg/dL or more. During follow-up, in the treat-to-target group, intensity was increased in patients with LDL-C levels of 70 mg/dL or more, maintained in patients with LDL-C levels of 50 mg/dL or more to less than 70 mg/dL, and decreased in patients with LDL-C levels less than 50 mg/dL. In the “high-intensity” group, maintenance of high-intensity statin therapy without adjustment was recommended, regardless of LDL-C levels during the study period.

Primary and secondary endpoints of the LODESTAR study.

The primary end point was serious adverse cardiac and cerebrovascular events, defined as a composite of death from all causes, myocardial infarction (MI), stroke, and coronary revascularization at 3 years. Death was classified as cardiovascular death and noncardiovascular death. Cardiovascular death was defined as death from myocardial infarction, sudden cardiac death, heart failure, stroke, cardiovascular surgery, cardiovascular hemorrhage, and any death in which a cardiovascular cause could not be excluded, as decided by the Clinical End Points Committee [12]. Myocardial infarction has been defined on the basis of clinical symptoms, electrocardiographic changes, or abnormal findings on imaging studies associated with an increase in creatine kinase myocardial band fraction above the upper normal limit or an increase in troponin T or troponin I level above the 99th percentile of the upper normal limit [13]. Stroke was defined as an acute cerebrovascular event that resulted in a neurological deficit of more than 24 hours or the presence of an acute infarct on imaging studies [14]. Each coronary revascularization procedure included percutaneous coronary intervention or coronary artery bypass grafting. Clinically indicated revascularization was defined as invasive angiographic percent diameter stenosis of 50% or more with ischemic symptoms or signs or percent diameter stenosis of 70% or more even in the absence of symptoms or signs [12]. Staged coronary revascularizations planned at randomization were not considered as adverse events.

Secondary end points were the occurrence of (1) new-onset diabetes, (2) hospitalization for heart failure, (3) deep vein thrombosis or pulmonary thromboembolism, (4) endovascular revascularization for peripheral artery disease, (5) aortic intervention or surgery, (6) end-stage renal disease, (7) discontinuation of study drugs because of intolerance, (8) cataract surgery, and (9) compilation of laboratory abnormalities.

Lipid-lowering therapy during the study period.

At the time of randomization, 74% of participants had a history of initial diagnosis or coronary revascularization of more than 1 year. Before randomization, 25% and 57% were taking a high-dose and a medium-dose statin, respectively. Of the 4400 participants, 4341 participants (98.7%) completed the 3-year clinical follow-up. The total number of years of follow-up was 6449 in the treat-to-target group and 6461 in the high-intensity group. Throughout the study period, in the treat-to-target group, statin intensity was up-titrated in 378 participants (17%), down-titrated in 208 patients (9%), and kept unchanged in 1614 participants (73%). In the target group, 53% were taking the high-dose statin at one year, 55% at two years, and 56% at three years; the corresponding rates in the high-dose statin group were 93%, 91%, and 89%, respectively (Fig. 1A). Throughout the study period, 43% of the target group received a moderate-intensity statin and 54% received a high-intensity statin. Ezetimibe was used more frequently in the treat-to-target group than in the high-intensity group from month six onward, mostly as combination therapy with high-intensity statin therapy (Fig. 1B) . Other cardiovascular medications did not differ statistically between groups during the study period.

At the six-week time point, mean (SD) LDL-C levels were significantly higher in the treat-to-target group than in the high-intensity statin therapy group (69.6 mg/dL vs. 66.8 mg/dL; difference, 2.8 mg/dL [95% CI, 1.3 to 4.3]; p<0.001). After six weeks, LDL-C levels no longer differed between groups. Throughout the study period, the mean (SD) LDL-C level was 69.1 mg/dL in the treat-to-target group and 68.4 mg/dL in the high-intensity group, which was not a significant difference (p=0.21). The proportion of participants with LDL-C levels below 70 mg/dL, the target group, was 55.7% at six weeks, 59.2% at three months, 57.7% at six months, 55.7% at one year, 60.8% at two years, and 58.2% at three years. This proportion was significantly lower in the target group than in the “high intensity” group after six weeks and three months.

Event rates of 8.1% vs. 8.7% at three years

The primary endpoint occurred in 177 participants (8.1%) in the treat-to-target group and 190 participants (8.7%) in the high-intensity group (absolute difference -0.6 percentage points; p<0.001 for non-inferiority). Deaths of all types occurred in 54 participants (2.5%) in the treat-to-target group and 54 (2.5%) in the high-intensity group (absolute difference <0.1%; p=0.99). Myocardial infarctions were observed in 34 participants (1.6%) and 26 participants (1.2%), respectively (absolute difference 0.4%; p=0.23). The incidence of stroke was also not statistically different between groups (0.8% vs. 1.3%; absolute difference -0.5%; p=0.13). This result was also consistent in the per-protocol population. The primary endpoint occurred in 8.3% of the treat-to-target group and 8.5% of the high-intensity group (absolute difference -0.2%; p<0.001 for non-inferiority).

None of the prespecified secondary end points differed statistically between groups. However, as a post-hoc secondary endpoint, a composite score of new-onset diabetes, aminotransferase or creatine kinase elevation, or end-stage renal disease was significantly lower in the treat-to-target group than in the high-intensity group (6.1% vs. 8.2%; absolute difference -2.1%; p = 0.009). These results were also consistent with those of the per-protocol population. The effect of the treat-to-target versus the high-intensity strategy was consistent for the primary endpoint in all subgroups.

Non-inferiority of the treat-to-target strategy confirmed

The LODESTAR trial demonstrated that a “treat-to-target” strategy, which provides lipid-lowering treatment with greater consideration of individual response to statin therapy, was “non-inferior” to a “high-intensity” strategy. Given nearly equal LDL-C levels in both groups, this is not surprising. It should be borne in mind that this comparison of strategies focused almost exclusively on treatment with statins. Combinations with non-statins such as ezetimibe for even greater LDL-C reduction played little role in the study. This could explain why in the group with target value strategy the LDL target range was not reached in many patients. In statin therapy, the conditions for a more consistent implementation of a “treat-to-target” strategy have now improved significantly with the availability of new lipid-lowering agents for combination with statins.

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