Assessing and Improving Prognosis in Patients with High Risk Acute Coronary Syndrome

Abstract

Endogenous fibrinolysis, if impaired, has been identified as a novel risk factor in patients with acute coronary syndrome (ACS). However, in-depth understanding of endogenous fibrinolysis, whether it varies day to day or reflective of a longer-term state, the relative importance of endogenous fibrinolysis in relation to different severity of coronary artery disease or if it can be modulated by pharmacotherapy remains unknown. I assessed variability in endogenous fibrinolysis in a group of 17 healthy volunteers. I showed that there was no diurnal variation in thrombotic or thrombolytic status, nor variability from week to week within the cohort of healthy volunteers, nor between male and female volunteers. This showed that there was no evidence of short-term variation of endogenous fibrinolysis in healthy volunteers. Subsequently, I assessed thrombotic status in 80 patients with chest pain and suspected coronary artery disease, with the aim of relating fibrinolytic status to the extent of coronary disease. Patients had a CT coronary calcium score and fibrinolytic status assessed using point-of-care testing. Platelet reactivity and endogenous fibrinolysis were unrelated to the extent of coronary calcification, but endogenous fibrinolysis was more impaired in patients with obstructive coronary disease than in patients without obstructive disease (Lysis time (LT): 2524 [2425 – 2623] vs. 1865 [1636 – 2256]s, p=0.0335). This indicates that flow-limiting stenoses, possibly through creating a prothrombotic environment, are related to impaired endogenous fibrinolysis. After this, I set out to investigate whether thrombotic status may differ amongst patients with different presentations of ACS. A total of 305 patients with ACS had blood tests to assess thrombotic and thrombolytic status: 143 ST-segment elevation myocardial infarction (STEMI), 125 Non-STEMI (NSTEMI) and 37 unstable angina (UA). Patients with NSTEMI exhibited the longest endogenous fibrinolysis time, compared to patients with other ACS presentations (LT: NSTEMI 2008 [1615 – 2503] vs. STEMI 1764 [1411 – 2326] vs. UA 1803 [1483 – 2186] s, p=0.0067). However, the difference was no longer significant when a propensity matched cohort of patients was studied (LT: NSTEMI 1869 [1580.5 – 2202] vs. STEMI 1978.5 [1609.5 – 2645.5] s, p=0.4832). This indicates that co-morbidities or cardiovascular risk factors may impact on the effectiveness of endogenous fibrinolysis. In a small case series of patients with myocardial infarction with non-obstructive coronary arteries (MINOCA), an effective endogenous fibrinolytic system may potentially explain, in part, the absence of occlusive disease on angiography. Lastly, I investigated the potential to modulate endogenous fibrinolysis using oral pharmacotherapy. In a randomised study, I assessed whether the addition of very low dose rivaroxaban could enhance fibrinolysis over and above that achieved with conventional dual antiplatelet therapy, in patients with acute coronary syndrome. The results showed that in patients with impaired endogenous fibrinolysis at presentation, this improved over time, irrespective of the antithrombotic medication prescribed. In particular, the addition of very low dose rivaroxaban did not improve endogenous fibrinolysis over and above that seen with dual antiplatelet therapy. Larger cohort studies will be required to investigate if there are truly no diurnal variation amongst healthy individuals including a comparison to patients with different diseases such as diabetes mellitus, stable chronic kidney disease and coronary artery disease to verify firstly, if this lack of variation holds true in stable diseased states and secondly, if the level of impairment increases with stable diseased states. Similarly, larger studies investigating endogenous fibrinolysis in patients with MINOCA may potentially provide further mechanistic insight into MINOCA with a coronary cause. With regards to high-risk patients with out-of-hospital cardiac arrest, the potential role of endogenous fibrinolysis as an added risk predictor could be explored further in a well organised large cohort study. Lastly, pharmacological modulation of endogenous fibrinolysis remains a potential novel pathway to prevent future cardiovascular events, but we may have to look beyond what the current pharmacological agents we have to offer.