Faculty Bibliography

BACKGROUND: The Universal Definition of Myocardial Infarction recommends the 99th percentile concentration of cardiac troponin in a normal reference population as part of the decision threshold to diagnose type 1 spontaneous myocardial infarction. Adoption of this recommendation in contemporary worldwide practice is not well known. METHODS: We performed a cohort study of 276 hospital laboratories in 31 countries participating in the National Heart, Lung, and Blood Institute-sponsored International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial. Each hospital laboratory's troponin assay manufacturer and model, the recommended assay's 99th percentile upper reference limit (URL) from the manufacturer's package insert, and the troponin concentration used locally as the decision level to diagnose myocardial infarction were ascertained. RESULTS: Twenty-one unique troponin assays from 9 manufacturers were used by the surveyed hospital laboratories. The ratio of the troponin concentration used locally to diagnose myocardial infarction to the assay manufacturer-determined 99th percentile URL was <1 at 19 (6.6%) laboratories, equal to 1 at 91 (31.6%) laboratories, >1 to 5 to 10 at 43 (14.9%) laboratories. The variability in troponin decision level for myocardial infarction relative to the assay 99th percentile URL was present for laboratories in and outside of the United States, as well as for high- and standard-sensitivity assays. CONCLUSIONS: There is substantial hospital-level variation in the troponin threshold used to diagnose myocardial infarction; only one-third of hospital laboratories currently follow the Universal Definition of Myocardial Infarction consensus recommendation for use of troponin concentration at the 99th percentile of a normal reference population as the decision level to diagnose myocardial infarction. This variability across laboratories has important implications for both the diagnosis of myocardial infarction in clinical practice as well as adjudication of myocardial infarction in clinical trials.

BACKGROUND: Lipoprotein(a) [Lp(a)] is an inherited atherogenic lipoprotein and an independent risk factor for atherosclerotic cardiovascular disease; however, its clinical role remains limited. OBJECTIVE: We hypothesized that Lp(a) screening in high cardiovascular risk patients could provide insight into disease pathogenesis and modify physician behavior for treatment intensification targeting traditional risk factors when Lp(a)-related risk was identified. METHODS: We screened 113 patients presenting electively for percutaneous coronary intervention (PCI) for Lp(a) who met any of the following criteria: (1) premature coronary artery disease (male age <55 years, female age <65 years); (2) family history of premature coronary artery disease; (3) progression to PCI despite well-controlled traditional risk factors (blood pressure <140/90 mm Hg, and low-density lipoprotein cholesterol <100 mg/dL, and HbA1c <7%, and nonsmoker); or (4) progression to PCI despite at least moderate intensity statin use (simvastatin 40, atorvastatin 40-80, or rosuvastatin 20-40 mg daily). RESULTS: In this high-risk cohort, Lp(a) was elevated in nearly half of all subjects, including those with seemingly well-controlled lipids by prior guidelines, suggesting a role for Lp(a) in conferring residual cardiovascular risk. In our cohort, when screened positive, knowledge of an elevated Lp(a) did not influence referring physicians' treatment intensification targeting traditional modifiable cardiovascular risk factors (P = .18). CONCLUSION: When screened judiciously, elevated levels of Lp(a) are highly prevalent in high cardiovascular risk patients, including at a young age, presenting for PCI and may contribute to previously unappreciated residual cardiovascular risk.

Background: Diabetes mellitus (DM) is a significant risk factor for cardiovascular events and peripheral artery disease (PAD). Purpose: This analysis investigated the additive risk of cardiovascular events in PAD with DM compared with PAD alone by assessing the DM population in Examining Use of tiCagreLor In paD (EUCLID) trial (NCT01732822). Methods: The EUCLID trial randomized 13,885 patients with PAD to monoantithrombotic treatment with ticagrelor 90mg twice daily or clopidogrel 75mg daily. Patients with abnormal ankle-brachial index (ABI) <=0.80 or toe-brachial index (TBI) <=0.60, or prior lower extremity revascularization were enrolled and followed up for a median duration of =30 months. The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction (MI) or ischemic stroke. The primary safety endpoint was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. This report details the risk of cardiovascular endpoints in the group of patients with DM (types 1 and 2) in EUCLID. Results: A total of 5345 patients (38.5%) enrolled in EUCLID had DM, of which 5134 (96%) had type 2 DM. At baseline, 36.5% of patients were treated with insulin (which could include other treatments), and 8.0% were treated with diet alone. The mean ABI (0.65 vs 0.65) and TBI (0.52 vs 0.55) were similar in those with and without DM. After adjustment for baseline characteristics, PAD patients with DM had significantly higher risk of the composite primary endpoint (5.0% vs. 3.7% /year, adjusted hazard ratio [HR] 1.34, 95% CI 1.14-1.57, p<0.001) but risk for major bleeding was similar (0.8% vs. 0.8% /year, HR 1.06, 95% CI 0.79-1.40, p=0.71) in comparison to PAD patients without DM. Conclusions: PAD patients with diabetes receiving potent antithrombotic therapy have a higher composite risk of cardiovascular death, MI, and stroke as compared with PAD patients without diabetes. The risk of major bleeding was similar among PAD patients with and without diabetes

PURPOSE: The EINSTEIN-Extension trial showed that an extended rivaroxaban treatment significantly reduced the risk for venous thromboembolic (VTE) recurrence. The present study assessed the risk for VTE recurrence and major bleeding associated with extended rivaroxaban treatment in a clinical practice setting among patients with VTE. METHODS: A retrospective study was conducted using claims data from February 2011 to April 2015. It included adult patients who initiated rivaroxaban therapy within 7 days after their first VTE and who continuously used rivaroxaban for at least 3 months (index date: end of initial 3-month treatment). Categorized into discontinued and continued cohorts, patients were followed up from the index date until the end of continuous treatment (continued cohort) or end of data or reinitiation of oral anticoagulant therapy (discontinued cohort). Using inverse probability of treatment weights controlling for confounders, adjusted Kaplan-Meier rates of recurrent VTE and major bleeding events were compared. FINDINGS: The analysis showed that, compared with the discontinued cohort (n = 1,536), the continued cohort (n = 5,933) had a significantly lower VTE recurrence rate after an additional 3 months (0.70% vs 1.70%), 6 months (1.41% vs 2.34%), 9 months (1.82% vs 3.01%), and 12 months (1.97% vs 3.01%) of treatment (all, p < 0.05). The difference in the cumulative event rates for major bleeding was not statistically significant. Similar results were obtained in an analysis among patients with VTE receiving rivaroxaban for >/=6 months. IMPLICATIONS: Our results suggest that, in clinical practice settings, patients with VTE who continued rivaroxaban therapy after the initial 3- or 6-month treatment period had a significantly lower risk for VTE recurrence without a statistically significant increased risk for major bleeding.

Von Willebrand disease (VWD) is an inherited bleeding disorder that often manifests clinically with hemorrhage after invasive procedures. We investigated the association between a diagnosis of VWD and bleeding and thrombotic outcomes following major non-cardiac surgery in a large national database from the United States. Patients age >/=45 years requiring major non-cardiac surgery were identified from Healthcare Cost and Utilization Project's National Inpatient Sample data. Von Willebrand disease, perioperative major adverse cardiovascular events (MACE), thrombotic events, and hemorrhage were defined by ICD9 diagnosis codes. From 2004 to 2013, a total of 10,581,621 hospitalizations for major non-cardiac surgery met study inclusion criteria and VWD was identified in 3765 (0.036%). In adjusted analyses, patients with VWD were significantly more likely to develop post-operative hemorrhage than patients without VWD (5.5 vs. 1.9%, p < 0.001; adjusted OR 3.49, 95% CI 3.03-4.03), but had similar odds of perioperative MACE and thrombotic events. Thus, a diagnosis of VWD was associated with increased risks of bleeding with non-cardiac surgery, without a corresponding reduction in perioperative thrombosis in comparison to patients without VWD. Perioperative management of patients with hereditary bleeding disorders and mitigation of thrombotic risks requires further study.

Background/UNASSIGNED:Venous thromboembolism (VTE) is a common vascular complication of non-cardiac surgery. Methods/UNASSIGNED:We evaluated national trends in perioperative in-hospital VTE incidence, management, and outcomes using a large database of hospital admissions from the United States. Patients aged ≥ 45 years undergoing major non-cardiac surgery from 2005 to 2013 were identified from the National Inpatient Sample. In-hospital perioperative VTE was defined as lower extremity deep vein thrombosis (DVT) or pulmonary embolism (PE), and the incidence was evaluated over time. Multivariable regression models with demographics and comorbidities as covariates were generated to estimate adjusted odds ratios (aOR). Results/UNASSIGNED:Major non-cardiac surgery was performed in 9,431,442 hospitalizations that met inclusion criteria, and perioperative VTE occurred in 99,776 patients (1,057 per 100,000), corresponding to an annual incidence of ≈53,000 after applying sample weights. Over time, perioperative VTE per 100,000 surgeries increased by 135 (95% CI 107 - 163), from 925 in 2005 to 1,060 in 2013 (p for trend <0.001; aOR [for 2013 versus 2005] 1.22, 95% CI 1.19 - 1.26), due to increases in non-fatal VTE rates (from 840 [per 100,000 surgeries] in 2005 to 987 in 2013; p for trend <0.001). Perioperative VTE occurred most frequently in patients undergoing thoracic (2.0%) and vascular surgery (1.8%). Mortality was higher in patients with VTE than those without VTE (aOR 3.12, 95% CI 3.05 - 3.20). Conclusions/UNASSIGNED:Perioperative VTE occurs in approximately 1% of patients ≥45 years undergoing major non-cardiac surgery, with increasing incidence of non-fatal VTE over time.

Background: Patients with peripheral artery disease (PAD) are at increased risk of atherothrombotic events and benefit from platelet inhibiting therapies. The EUCLID trial demonstrated no significant benefit from ticagrelor versus clopidogrel for the reduction of cardiovascular or limb events in patients with PAD. Aims: The EUCLID platelet substudy aimed to compare the antiplatelet effects of ticagrelor and clopidogrel in patients with PAD. Methods: Patients were randomized to receive either clopidogrel (75 mg daily) or ticagrelor (90 mg twice daily). The effect of study drug was studied in 75 patients during maintenance therapy (>=6-weeks post randomization). In 42 patients, platelet inhibition was measured at baseline and after 2-and 6-weeks of study drug (=12 hrs after last dose). In all patients, pharmacodynamic assessments were made using light transmission aggregometry (in response to ADP 5 and 20uM, collagen 1ug/ml and arachidonic acid [AA] 150uM), VerifyNow P2Y12, and VASP phosphorylation. Results: During maintenance therapy, ticagrelor achieved lower platelet activity of ADP-induced platelet aggregation than clopidogrel (maximum platelet aggregation to ADP 5uM, 39% vs. 60. 5%, P< 0. 001; ADP 20uM 51% vs. 67. 5%, P=0. 004; VerifyNow, 74 vs. 165 PRU, P< 0. 001; VASP 16. 9 vs. 45. 8 PRI, P< 0. 001). High on-treatment platelet reactivity was observed more frequently in the clopidogrel treated group (P< 0. 05 for each ADP-mediated assay). The effect at 14-days and 6-weeks was consistent with a greater platelet inhibition with ticagrelor compared with clopidogrel. The inhibition of collagenor AA-induced platelet aggregation was not different between groups. Conclusions: In patients with PAD, ticagrelor achieved greater inhibition of ADP mediated platelet activity versus clopidogrel. The inhibition of non-ADP mediated platelet activity was not different between groups. Despite greater platelet inhibition, ticagrelor was not superior to clopidogrel for the reduction of cardiovascular events in patients with PAD

Danish nationwide registries were used to investigate temporal trends in initiation of rivaroxaban or apixaban or dabigatran versus vitamin K antagonists (VKA) in patients with venous thromboembolism (VTE). Patients treated with one of the NOACs (rivaroxaban, dabigatran, apixaban) or VKA were identified between February 2012 and September 2016. A total of 19,578 patients were included of which 10,844 (55.4%) were treated with VKA and 8,734 (44.6%) were treated with NOACs (rivaroxaban 7,572, apixaban 1,066, and dabigatran 96). Temporal trends showed a decrease in the initiation of VKA (p-value for decreasing trend, p < 0001) and an increase in the initiation of rivaroxaban and apixaban (p-value for increasing trend, p < 0001). By September 2016, 12%, 70%, 16%, and 2% of patients with VTE were initiated on VKA, rivaroxaban, apixaban, and dabigatran. Patients with previous VTE, chronic kidney disease, liver disease, cancer, and thrombophilia were more likely to be initiated on VKA compared with one of the NOACs. In conclusion the initiation of rivaroxaban and apixaban is increasing significantly over time in patients with VTE. Patients with previous VTE, chronic kidney disease, liver disease, cancer, and thrombophilia were more likely to be initiated on VKA compared with rivaroxaban or apixaban.

Platelets play a critical role in atherogenesis and thrombosis-mediated myocardial ischemia, processes that are accelerated in diabetes. Whether hyperglycemia promotes platelet production and whether enhanced platelet production contributes to enhanced atherothrombosis remains unknown. Here we found that in response to hyperglycemia, neutrophil-derived S100 calcium-binding proteins A8/A9 (S100A8/A9) interact with the receptor for advanced glycation end products (RAGE) on hepatic Kupffer cells, resulting in increased production of IL-6, a pleiotropic cytokine that is implicated in inflammatory thrombocytosis. IL-6 acts on hepatocytes to enhance the production of thrombopoietin, which in turn interacts with its cognate receptor c-MPL on megakaryocytes and bone marrow progenitor cells to promote their expansion and proliferation, resulting in reticulated thrombocytosis. Lowering blood glucose using a sodium-glucose cotransporter 2 inhibitor (dapagliflozin), depleting neutrophils or Kupffer cells, or inhibiting S100A8/A9 binding to RAGE (using paquinimod), all reduced diabetes-induced thrombocytosis. Inhibiting S100A8/A9 also decreased atherogenesis in diabetic mice. Finally, we found that patients with type 2 diabetes have reticulated thrombocytosis that correlates with glycated hemoglobin as well as increased plasma S100A8/A9 levels. These studies provide insights into the mechanisms that regulate platelet production and may aid in the development of strategies to improve on current antiplatelet therapies and to reduce cardiovascular disease risk in diabetes.