Prediction of the Population at Risk of Atherothrombotic Disease: A Three Step Approach

The mainstay of the prevention of atherothrombotic disease (ATD, which is atherosclerotic disease, with emphasis on the thrombosis that so often precipitates the acute ATD event, such as acute myocardial infarction, acute cerebral infarction, aortic aneurysm, etc) is the prediction of the population at risk of ATD. There are many predictive tools, all of which use the same general risk factors, but the one favored by the author is the Bowling Green Study (BGS) graph.. This graph is based on the ATD risk factor constellations of 870 people in Bowling Green, Ohio, the county seat of Wood County, in northwest Ohio. (There is one other patient who has full lipid data and blood pressure data, but whose cigarette smoking status is not known.) The ordinate of the graph is the lipid arm and consists of the Cholesterol Retention Fraction (CRF, defined as [LDL-HDL]/LDL). HDL refers to high-density lipoprotein cholesterol and LDL refers to low-density lipoprotein cholesterol. The abscissa of the graph is the blood pressure arm, represented by the systolic blood pressure (SBP). This graph was initially developed in 1981 (using the LDL:HDL ratio) then modified in 1983 (using the CRF), and, by 1988, the author was able to generate a threshold line, which separated the main stream of ATD patients’ CRF-SBP plots from those of a few outliers. (The threshold line is not a regression line, but rather a divider, based on the principle of the fewest false negatives.) The 1988 threshold line was modified in 2000 to its present location at CRF-SBP loci (0.74, 100) and (0.49, 140). Many of the various ATD risk predictors are complex and difficult to use, whereas the graph is simple to use and based on the risk factor constellations of actual ATD patients, wherein lies its value.

Antithrombotic Therapy for Atrial Fibrillation and Coronary Artery Disease in Patients With Prior Atherothrombotic Disease: A Post Hoc Analysis of the AFIRE Trial

Background Among patients with atrial fibrillation and stable coronary artery disease, those with histories of atherothrombotic disease are at high‐risk for future ischemic events. This study investigated the efficacy and safety of rivaroxaban monotherapy in patients with atrial fibrillation, coronary artery disease, and histories of atherothrombotic disease. Methods and Results This was a post hoc subanalysis of the AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial. Patients with non‐valvular atrial fibrillation and coronary artery disease were recruited and randomized to receive the rivaroxaban monotherapy or combination therapy with rivaroxaban plus antiplatelet drug. For the purpose of this sub‐study, participants were divided into 2 subgroups, including the atherothrombosis group (those with histories of myocardial infarction, stroke, and/or peripheral artery disease; n=1052, 47.5%) and non‐atherothrombosis group (n=1163, 52.5%). The efficacy end point included cardiovascular events or all‐cause death, while the safety end point was major bleeding. Net adverse events consisted of all‐cause death, myocardial infarction, stroke, or major bleeding. In the atherothrombosis group, rivaroxaban monotherapy was significantly associated with a lower risk of net adverse events when compared with combination therapy (hazard ratio [HR], 0.50; 95% CI, 0.34–0.74; P <0.001), with a decrease in both efficacy (HR, 0.68; 95% CI, 0.47–0.99; P =0.044) and safety (HR, 0.37; 95% CI, 0.19–0.71; P =0.003) end points. By contrast, there were no differences between treatment outcomes for the non‐atherothrombosis group. Conclusions Rivaroxaban monotherapy significantly reduced net adverse events as compared with combination therapy for patients with atrial fibrillation, coronary artery disease, and prior atherothrombotic disease. Registration URL: https://www.umin.ac.jp/ctr/ ; Unique identifier: UMIN000016612. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02642419.

Cardiovascular Biomarkers and Heart Failure Risk in Stable Patients With Atherothrombotic Disease: A Nested Biomarker Study From TRA 2°P‐TIMI 50

Background Patients with stable atherothrombotic disease vary in their risk of developing heart failure (HF). Circulating cardiovascular biomarkers may improve HF risk assessment and identify patients who may benefit from emerging HF preventive therapies. Methods and Results We measured high‐sensitivity cardiac troponin I and BNP (B‐type natriuretic peptide) in 15 833 patients with prior myocardial infarction, ischemic stroke, or peripheral artery disease from the TRA 2°P‐TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events‐Thrombolysis in Myocardial Infarction 50) trial, excluding patients with recent myocardial infarction (<30 days). Biomarkers were categorized using a priori cut points. Hospitalization for HF (HHF) end points were adjudicated with blinded structured review of serious adverse events. Associations between biomarkers and HHF outcomes were adjusted for sex and independent clinical risk predictors of HHF in our cohort (age ≥75, prior HF, type 2 diabetes mellitus, polyvascular disease, body mass index, anemia, chronic kidney disease, hypertension). Baseline high‐sensitivity cardiac troponin I and BNP each identified a significant graded risk of HHF independent of clinical risk predictors, including in the subgroups of patients with and without type 2 diabetes mellitus and with and without prior HF. Patients with both high‐sensitivity cardiac troponin I ≥5 ng/L and BNP ≥100 pg/mL had the highest HHF event rates. When added to a multivariable Cox regression model with clinical risk predictors (C‐index 0.88; 95% CI, 0.85–0.90), BNP (C ‐index 0.92; 95% CI, 0.90–0.93), and high‐sensitivity cardiac troponin I (C‐index 0.90; 95% CI, 0.88–0.92) each significantly improved the prognostic performance of the model (both P LRT <0.001). Conclusions Biomarkers of myocardial injury and hemodynamic stress are independent predictors of HHF risk in patients with stable atherothrombotic disease, with and without prior HF and/or type 2 diabetes mellitus. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00526474.

Abstract WP244: Applicability of the Compass Trial Criteria Among Stable Outpatients With Established Atherothrombotic Disease or Major Risk Factors

Background and Purpose: The objective of this study were to describe the proportion of patients eligible for the COMPASS trial among stable outpatients with either established atherothrombotic disease or major vascular risk factors, and to analyze 6-month incident stroke risk according vascular risk factors at baseline. Methods: We prospectively recruited 5,101 stable outpatients in 172 sites, within the Mexican INDAGA cohort study. Inclusion criteria were age >18 years and established atherothrombotic disease [history of either acute coronary syndromes (ACS), acute ischemic stroke (AIS)/transient ischemic attack (TIA) or peripheral artery disease (PAD)] or major vascular risk factors (age <55 years plus ≥2 major vascular risk factors, or age ≥55 years plus ≥1 vascular risk factors). Among these patients, we applied the selection criteria of the COMPASS trial for analysis, dividing the population in no COMPASS criteria met and COMPASS criteria met, and this last group subdivided among patients with previous AIS/TIA and without this antecedent, in order to stratify the risk for stroke during 6-month follow-up (incident AIS/TIA). Results: Among 5,101 stable outpatients with either established atherothrombotic disease (n=2,827) or major vascular risk factors (n=2,274), a total of 1,927 (37.8%) met COMPASS trial criteria: 1,054 (54.7%) with established cerebrovascular disease (past history of AIS/TIA) and 873 (45.3%) without. During 6-month follow-up, there were 89 incident AIS/TIA (39 AIS and 54 TIA): 1.7% among the whole population and 2.2% among the COMPASS subgroup. AIS/TIA occurred in a similar frequency among the COMPASS subgroup with established cerebrovascular disease (1.6%) and COMPASS without cerebrovascular disease (0.9%) (P=0.18). After a Cox-proportional hazards model, independent predictors of incident AIS/TIA were age ≥65 years (HR: 1.99, 95% CI: 1.29-3.07) and established cerebrovascular disease at baseline (HR: 1.61, 95% CI: 1.02-2.53). Conclusions: The majority of stable outpatients at vascular risk met COMPASS selection criteria and could be good candidates for low-dose rivaroxaban in addition to aspirin. Short-term predictors of AIS/TIA were old age and history of cerebrovascular disease

Burden of Coronary Artery Disease and Peripheral Artery Disease: A Literature Review

Background. Atherothrombotic disease, including coronary artery disease (CAD) and peripheral artery disease (PAD), can lead to cardiovascular (CV) events, such as myocardial infarction, stroke, limb ischemia, heart failure, and CV death. Aim. Evaluate the humanistic and economic burden of CAD and PAD and identify unmet needs through a comprehensive literature review. Methods. Relevant search terms were applied across online publication databases. Studies published between January 2010 and August 2017 meeting the inclusion/exclusion criteria were selected; guidelines were also included. Two rounds of screening were applied to select studies of relevance. Results. Worldwide data showed approximately 5–8% prevalence of CAD and 10–20% prevalence of PAD, dependent on the study design, average age, gender, and geographical location. Data from the REACH registry indicated that 18–35% of patients with CAD and 46–68% of patients with PAD had disease in one or more vascular beds. Use of medication to control modifiable CV risk factors was variable by country (lower in France than in Canada); statins and aspirin were the most widely used therapies in patients with chronic disease. Survival rates have improved with medical advancements, but there is an additional need to improve the humanistic burden of disease (i.e., associated disability and quality of life). The economic burden of atherothrombotic disease is high and expected to increase with increased survival and the aging population. Conclusion. CAD and PAD represent a substantial humanistic and economic burden worldwide, highlighting a need for new interventions to reduce the incidence of atherothrombotic disease.

Genetic Polymorphisms Associated with Thrombotic Disease Comparison of Two Territories: Myocardial Infarction and Ischemic Stroke

Background and Purpose. The thrombin-activatable fibrinolysis inhibitor (TAFI) is an important inhibitor of fibrinolysis and plays a critical role in the pathogenesis of arterial thrombosis; genetic polymorphisms of the TAFI gene affect its activity and increase the risk of thrombosis. Moreover, studies in young patients are still scarce. The aim was to examine the contribution of the Thr325Ile and Ala147Thr polymorphisms with ST acute myocardial infarction (STEMI) or idiopathic ischemic stroke (IIS) in the young Mexican population. Methods. A total of 244 patients with STEMI ≤45 years of age and 244 controls. In a second study, 250 patients with IIS ≤45 years of age were recruited, including 250 controls. In both studies, cases and controls were matched by age and sex. The polymorphisms were determined in all participants by PCR-RFLP. Results. There was significant difference in the Thr325Ile genotype distribution (P=0.001) and allele frequency (P=0.001) between STEMI and control groups, but no difference in the Ala147Thr genotype distribution (P=0.24) and allele frequency (P=0.46), neither in the Thr325Ile genotype distribution (P=0.25) nor in the Ala147Thr genotype distribution (P=0.46) or their allele frequencies; there was significant difference between IIS and the control group. There were independent factors for STEMI: the Ile allele (P=0.01), type 2 diabetes mellitus (P=0.001), hypertension (P=0.001), smoking (P=0.001), dyslipidemia (P=0.001), and family history of atherothrombotic disease (P=0.001). The independent factors for IIS were hypertension (P=0.001), smoking (P<0.01), and family history of atherothrombotic disease (P<0.01). Conclusions. The Thr325Ile polymorphism, but no Ala147Thr polymorphism, represents an independent risk factor for STEMI in the young Mexican population.