Intensive LDL-C lowering benefits more for patients hitting ≥100 mg/dL at baseline
More intensive lowering of LDL-C levels was associated with a progressively greater survival benefit than less intensive approach, when the baseline LDL-C levels were ≥100 mg/dL, reveals a meta-analysis of 34 randomized trials.
“This association was not present when baseline LDL-C level was less than 100 mg/dL, suggesting that the greatest benefit from LDL-C–lowering therapy may occur for patients with higher baseline LDL-C levels,” the researchers stated.
The findings argue against using LDL-C targets exclusively to guide therapy, and challenge the concept of intensive lowering of LDL-C to achieve extremely low LDL-C levels.
“The results … are quite provocative and, if true, would have significant implications for current clinical care guidelines and algorithms,” commented Drs Ann Navar and Eric Peterson of Duke Clinical Research and Duke University Medical Center, Durham, North Carolina, US, respectively in an editorial. [JAMA 2018;319:1549-1551]
More benefits with higher baseline LDL-C
The 34 trials included in the meta-analysis comprised eight randomized trials in primary prevention, 16 in secondary prevention, and 10 in both settings, with a mean follow-up of 3.9 years. A total of 136,299 patients were randomized to more intensive LDL-C-lowering therapy and 133,989 to less intensive treatment or placebo. [JAMA 2018;319:1566-1579]
The researchers found that the higher the baseline LDL-C, the greater the reductions in risk of all-cause and cardiovascular (CV)-related mortality with a more intensive vs a less intensive therapy, but only when baseline LDL-C levels were ≥100 mg/dL (p<0.001 for interaction).
Among the trials with baseline LDL-C ≥100 mg/dL, intensive LDL-C lowering was associated with a 9 percent lower risk of all-cause mortality (rate ratio [RR], 0.91; p<0.001) and a 14 percent lower risk of CV mortality (RR, 0.86; p<0.001) for every 40 mg rise in baseline LDL-C.
Reduction in the risk of all-cause mortality with intensive treatment was greatest in trials enrolling participants with baseline LDL-C levels of ≥160 mg/dL (RR, 0.72; p<0.001).
Similarly, risk reductions in the secondary endpoints of major adverse cardiac events (MACE), myocardial infarction (MI), and revascularization associated with intensive treatment were also progressively greater with higher baseline LDL-C levels. Unlike the coprimary mortality endpoints, the association between intensive therapy and reductions in risk of the secondary endpoints remained even when baseline LDL-C was <100 mg/dL.
Findings with caveats
“If the authors’ trial-level conclusions are confirmed to apply to individual patients, clinicians (and payers) may have a strong biological basis for limiting therapy and access to potent but costly lipid-lowering drugs such as PCSK9* inhibitors to patients with LDL-C levels above certain thresholds,” suggested Navar and Peterson.
“Yet before accepting these conclusions, patients and clinicians need to consider whether an ecological fallacy may confound the trial meta-analysis,” they cautioned, referring to the caveat that drawing conclusions about an individual based on group-level characteristics may be inappropriate.
As the investigators acknowledged, the meta-analysis included only data from the trial level and not individual level, which constitutes one of the study limitations.
“Because the individual-level data were not analysed, the study cannot say definitively whether the observed treatment differences were attributable to effect modification by baseline LDL-C level or whether this association is confounded by other trial-related differences,” wrote Navar and Peterson. Although the researchers attempted to adjust for potential confounders, there are still limitations to the adjustments.
“One of the most powerful potential confounders may be temporal changes in clinical care,” they highlighted, pointing out that recent trials showed lower rates of mortality for acute MI than earlier trials conducted more than two decades ago, partly due to better secondary prevention measures such as antiplatelet and antihypertensive therapies over time. Also, differences between trials such as design and follow-up duration may influence the chances of detecting an overall mortality benefit.
Moving forward, an updated analysis using individual-participant data would help to elucidate whether “the benefits of lipid lowering represents a true biological phenomenon or is an artefact of the ecology of the trials,” suggested the editorialists.
“When selecting patients for more intensive lipid-lowering therapies, clinicians should consider both a patient’s initial LDL-C level but also the patient’s overall risk for CVD events,” advised Navar and Peterson. “Multiple factors beyond LDL-C affect risk of downstream events including age, blood pressure, diabetes, and extent of vascular disease. Thus, patients with high overall CVD risk may achieve large absolute risk reductions, even if their potential relative risk reduction with therapy is blunted by lower starting LDL-C levels.”