Prof. Lars Wallentin,
Dr. Valentin Fuster,
By Lars Wallentin, FESC (Uppsala, Sweden)View Discussant reportOpen the PresentationWatch the Webcast
List of Authors: Lars Wallentin, Ralph A. H. Stewart, Claes Held, Rebekkah Brown, Christopher P. Cannon, Wolfgang Koenig, Ph. Gabriel Steg, Olof Petter Östlund, Agneta Siegbahn, Harvey D. White for the STABILITY Investigators
BackgroundElevated lipoprotein-associated phospholipase A2 (Lp-PLA2) activity promotes development of vulnerable atherosclerotic plaques. Increasing plasma levels of Lp-PLA2 activity are associated with increased risk of coronary events. The STABILITY study evaluated if 3 - 5 years treatment with darapladib, a selective, oral inhibitor of Lp-PLA2 activity, reduced major coronary events in patients with stable coronary artery disease. The results of the trial (White H et al N Engl J Med. 370(18):1702-11, 2014) showed that darapladib did not reduce the primary outcome (cardiovascular death, myocardial infarction or stroke) HR 0.94 (0.85-1.03), p=0.199 but provided a nominal reduction of the secondary endpoint of major coronary events, HR 0.90 (0.82-1.00), p=0.045. In this predefined study we elucidated if Lp-PLA2 activity was prognostic for outcomes, if darapladib persistently reduced Lp-PLA2 activity and if high Lp-PLA2 activity identified patients with larger benefits of darapladib treatment.MethodsThe STABILITY trial included 15828 patients in 39 countries with evidence of stable coronary heart disease documented by one of the following: prior myocardial infarction, prior percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), or multi-vessel coronary artery disease.In addition at least one of the following additional predictors of cardiovascular risk was required: age 60 years or older; diabetes requiring pharmacotherapy; high-density lipoprotein (HDL) cholesterol less than 1.03 mmol/L (40 mg/dl); current smoking; moderate renal dysfunction; or polyvascular arterial disease. The patients were randomized to darapladib 160 mg once daily or placebo and followed for a median of 3.7 years. The primary end point was time to first occurrence of cardiovascular (CV) death, myocardial infarction (MI), or stroke. Secondary end points included major coronary events (comprising coronary heart disease death, myocardial infarction, or urgent coronary revascularization for myocardial ischemia).Blood samples were available in most patients at baseline and also 24 hours after last intake of study drug, at months 1, 3, 6, 18 and End-of-Treatment. Plasma aliquots were stored at -70oC until biochemical analyses. Lp-PLA2activity was measured in 14,500 patients at baseline and in a subset of 100 patients with samples available at all follow-up visits. Measurements were performed with the PLAC® test for Lp-PLA2 Activity kit run in an automated clinical chemistry analyzer. The assay is manufactured by diaDexus, Inc. available in Europe as a CE mark kit and a RUO product in USA.ResultsThe Lp-PLA2 activity levels were related to cardiovascular outcomes with a significantly higher risk, HR 1.45 (1.25 – 1.69), P <0.001, in the highest tertile (> 192.5 nmol/min/ml) compared with the lowest tertile, concerning the composite of CV-death, MI and stroke in multivariable analysis. Darapladib treatment provided a persistent around 65% reduction of the Lp-PLA2activity during treatment. There was no significant interaction between the tertiles of Lp-PLA2and the effects of darapladib either on the primary or secondary outcomes (Table 1).
ConclusionsIn patients with stable CHD followed for 3.7 years on a background of optimal medical therapy Lp-PLA2 activity is an independent risk marker for cardiovascular events. Darapladib treatment provides a persistent reduction of the Lp-PLA2 activity of about 65% during treatment. However, the Lp-PLA2 activity at baseline does not predict the effects of darapladib treatment on cardiovascular events.
By Valentin Fuster, FESC (New York, United States of America)See Presenter abstractOpen the presentationWatch the Webcast
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