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Lipoprotein(a), or Lp(a), at levels well below currently accepted risk thresholds correlated with increased cardiovascular risk in a large registry study, suggesting a wider patient pool that could benefit from future preventive therapies.

Although guidelines endorse the 80th percentile cutoff of 125 nmol/L to identify higher-risk candidates for initiation or intensification of preventive therapies such as statins, any plasma Lp(a) level above the median significantly correlated with long-term major adverse cardiovascular events (MACE) in real-world patients with baseline atherosclerotic cardiovascular disease (ASCVD) in the Mass General Brigham Lp(a) Registry.

MACE risk over more than a decade was 14% higher among those in the 51st to 70th percentiles 42-111 nmol/L (adjusted HR 1.14, 95% CI 1.05-1.24) compared with average or lower Lp(a). The adjusted hazard ratio rose to 1.21 for the 71st to 90th percentile (112-215 nmol/L) and leveled off thereafter.

As for those without established ASCVD, an upward trend for MACE risk with increasing Lp(a) only reached statistical significance at the highest Lp(a) levels (aHR 1.93 for the 91-100th percentile, 95% CI 1.54-2.42), reported Ron Blankstein, MD, of Brigham and Women's Hospital in Boston, and colleagues in the .

"Across both primary and secondary prevention groups, there was a meaningful increase in ASCVD risk with increasing Lp(a) levels, with the excess risk being strongest for MI [myocardial infarction] and coronary revascularization," Blankstein's team wrote.

"These insights can guide both current clinical risk assessment as well as future trials for Lp(a)-lowering therapies as we have identified populations of patients (both primary and secondary prevention) who would not be included in current Lp(a) trials but have significant residual Lp(a) attributable risk," the group concluded.

Lp(a) is a highly atherogenic particle and known independent risk factor for ASCVD. Nevertheless, due to Lp(a) historically being considered an unmodifiable cardiovascular risk factor, universal screening is not endorsed by U.S. guidelines and is infrequently performed.

"However, with the advent of small interfering RNAs and antisense oligonucleotides, the landscape of novel therapeutics is showing significant promise," Blankstein and colleagues noted.

They cited two ongoing phase III trials studying novel Lp(a)-lowering therapies: on pelacarsen injected monthly and on olpasiran injected every 12 weeks. Whereas both studies focus on secondary prevention patients, minimum baseline Lp(a) entry requirements differ, at 175 and 200 nmol/L in the two studies respectively.

Study authors suggested "that there will likely be a significant population of individuals with and without baseline ASCVD who remain at increased cardiovascular risk from Lp(a) who will not be included in these trials. Thus, in addition to ongoing clinical trials, additional studies are needed to further elucidate how Lp(a) can affect risk in various populations, and whether the excess risk attributable to Lp(a) can be effectively lowered."

Nathan Wong, PhD, MPH, of the University of California Irvine, similarly urged investigation of Lp(a) in broader populations and predicted that "it may not be long before guidelines in the United States endorse universal screening, which many experts already support."

"The identification of patients at increased risk for ASCVD, in both primary and secondary prevention, remains an important challenge and priority," he wrote in an . "The failure to screen and identify those with Lp(a)-associated risks represents a missed opportunity to address this risk, not only with our existing repertoire of treatments but hopefully in the future with the development of promising therapies targeting Lp(a)."

The present cohort study comprised patients with Lp(a) readings taken as part of routine care from 2000 to 2019 at two large Boston medical centers.

Altogether, the registry included 16,419 people followed for a median of 12 years (median age 60 years, 41% women). Approximately 62% had baseline ASCVD, and this group tended to have higher Lp(a) levels compared with those without ASCVD (37.8 vs 31.1 nmol/L, P<0.001).

MACE events counted during follow-up were MI, stroke, coronary revascularization, and cardiovascular mortality. Ultimately, 6.5% of individuals studied experienced a nonfatal MI, 8.4% a nonfatal ischemic stroke, 8.3% underwent coronary revascularization, and 14.7% died of cardiovascular causes.

Blankstein's group acknowledged the potential for residual confounding and biases due to the retrospective design of the study. Additionally, the authors were unable to account for genetic or inflammatory biomarkers.

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