Atherosclerosis Clinical Trial
Official title:
Assessment of Lipoprotein(a) and Endogenous Fibrinolysis in Atherosclerotic Cardiovascular Disease/Aortic Valve Disease
Prior studies have shown that impaired endogenous fibrinolysis is a novel, independent cardiovascular risk factor in patients with myocardial infarction and there is currently no known chronic treatment to enhance endogenous fibrinolysis. To date, no therapies have been able to sufficiently reduce Lp(a) and therefore it was considered to be a non-modifiable cardiovascular risk factor. New data, however, has shown that PCSK9 inhibitors and inclisiran (medication that you have been deemed eligible for in order to help further reduce your cholesterol levels) to reduce Lp(a) levels by approximately 20-25%. The aim of this study to is to assess: 1. if there is an association between raised Lp(a) level in blood and the effectiveness of endogenous fibrinolysis (lysis time). 2. whether lowering Lp(a) with PCSK9i or inclisiran can enhance endogenous fibrinolysis
The risk of a clot forming in a blood vessel, which can cause a heart attack or stroke, is determined partly by how "sticky" the blood is and partly by the effectiveness of the natural defences in the blood in dissolving any clots that start forming (clot lysis, or "fibrinolysis"). In the last few years, using new blood testing techniques, we and other groups, have shown that individuals who have less effective natural clot lysis, have a much higher risk of heart attack, stroke and death, even despite current best medications. Therefore, we would like to find medications that can make clot lysis more effective, in such individuals, to reduce their risk of stroke and heart attack. Unfortunately, most blood thinning tablets for long term use do not improve clot lysis. Earlier, our group has shown that the anticoagulant apixaban, mildly improved clot lysis Elevated concentration of Lp(a) in the blood is a risk factor for the development of cardiovascular disease including coronary artery disease and narrowing of the aortic valve. Lp(a) may exert its adverse effects by impairing fibrinolysis. Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, including fibrin clots. Lp(a) has a high degree of homology to plasminogen (a pro-enzyme that is cleaved to form plasmin) and may cause thrombosis by competitively inhibiting t-PA-mediated plasminogen activation and tPA-mediated clot lysis. Furthermore, Lp(a) stimulates the activity of PAI-1, which is the major inhibitor of the fibrinolytic system. Until recently, Lp(a) has been considered a non-modifiable cardiovascular risk factor as few therapies are available to sufficiently reduce Lp(a) levels. New data, however, have shown that novel cholesterol lowering treatments, namely PCSK9 inhibitors and inclisiran (a long-acting silencing RNA) can reduce Lp(a) levels by approximately 20-25%. Given Lp(a) is a causal risk factor for cardiovascular outcomes, it is important to know if a reduction in Lp(a) can favourably modify endogenous fibrinolysis. If Lp(a) level is directly related to the effectiveness of endogenous fibrinolysis, then medications that reduce Lp(a) (currently PCSK9i and/or inclisiran, and others in development) could be used as targeted treatment for patients who despite optimal antithrombotic therapy, demonstrate impaired endogenous fibrinolysis. ;
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