**8. Conclusion**

Imaging Study (IBIS)-2 [98]. It was a multicenter, randomized, double-blind placebo-control‐ led study that included 330 patients with angiographically confirmed coronary artery disease. Inhibition of Lp-PLA2 with darapladib also prevented necrotic core expansion of coronary

One multicenter, randomized, double-blind placebo-controlled study examined the effects of darapladib on biomarkers of cardiovascular risk in 959 CAD and CAD-risk equivalent patients who were previously randomized to atorvastatin 20 mg or 80 mg and then randomized to oral darapladib 40, 80, 160 mg, or placebo for 12 weeks. Overall dose-dependent inhibition of Lp-PLA2 activity was sustained over the study period and was present in both atorvastatin dose groups, at different baseline LDL cholesterol < or ≥70 mg/dl, and high-density lipoprotein

The first study that examined the effects of darapladib on Lp-PLA2 activity in Japanese dyslipidemic patients with/without the Val279Phe single-nucleotide polymorphism (SNP) of the *PLA2G7* gene showed that darapladib produced sustained inhibition of Lp-PLA2

Two large-scale studies with hard clinical endpoints were completed: the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial, with 15,828 randomized patients, and the Stabilization of Plaques using Darapladib-Thrombolysis In Myocardial Infarction 52 Trial (SOLID-TIMI 52), with an estimated recruitment of 13,026

The SOLID-TIMI 52 was a randomized, double-blind, placebo-controlled, multicenter, and event-driven trial that determined the clinical benefit of direct inhibition of Lp-PLA2 activity with darapladib in patients after an acute coronary syndrome (non-ST-elevation or STelevation myocardial infarction). Subjects were randomized to darapladib (160 mg entericcoated tablet daily) or matching placebo within 30 days after acute coronary syndrome. The primary endpoint was the composite of coronary heart disease death, nonfatal myocardial infarction, or nonfatal stroke, and secondary endpoints were major and total coronary events, individual components of the primary endpoint, and all-cause mortality. Patients were followed up for a median of 2.5 years. In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within

The STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial was a double-blind trial in patients randomized more than one month after a myocardial infarction to double-blind darapladib (160 mg daily) or placebo (daily). The primary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end‐ points included the components of the primary endpoint as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revasculariza‐ tion for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization). Patients were followed up for a median of 3.7 years. In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite endpoint of

30 days of hospitalization did not reduce the risk of major coronary events.

cardiovascular death, myocardial infarction, or stroke.

plaque as measured on intravascular ultrasound.

cholesterol HDL-C < or ≥40 mg/dl [99].

122 Lipoproteins - From Bench to Bedside

activity [100].

patients [101-103].

Within the last decade, a broad range of biomarkers associated with an increased risk for death and cardiovascular/cerebrovascular endpoints have been identified. Epidemiological studies clearly indicated that Lp-PLA2 has the potential to become a clinically useful biomarker because it promotes independent information in the diagnosis, and especially cardiovascular/ cerebrovascular risk stratification. In the future, we can expect new drugs (new Lp-PLA2 inhibitors) that will affect patient's management, and assessing the effect of Lp-PLA2 inhibition on cardiovascular endpoints can provide definitive answers.

However, further clinical validation in well-designed observational and interventional studies is needed before these recommendations can be properly evaluated in order to include them in the clinical diagnostic algorithms.

Currently, Lp-PLA2 measurement has only been reserved to patients with moderate and high cardiovascular risk, rather than healthy population or low-risk patients, since the values of Lp-PLA2 in these population groups are insignificant. Also, the evaluation of Lp-PLA2 in combi‐ nation with noninvasive imaging could be expected. The formation of best-case model from Lp-PLA2 and other biomarkers can yield the best patient stratification algorithm. The next step could be cost-effectiveness analysis of more accurate risk stratification with biomarker testing. Future studies need to focus on exploring the potential of this biomarker and evaluating the effects of Lp-PLA2 inhibition on human populations.

The final decision on which test to use for Lp-PLA2 determination, test based on mass or activity of Lp-PLA2, together with the development of commercially available automated, robust, valid, high throughput, cost-effective test capable of increasing agility and reducing the analytical imprecision can be adopted routinely in clinical practice for better risk stratification and therapeutic choice in patients with cardiovascular/cerebrovascular disease.
