Challenges of antithrombotic treatment in high-risk populations and a fond farewell to CKMB

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on thrombosis and antithrombotic treatment contains a State of the Art Review article entitled ‘Antithrombotic therapy in diabetes: which, when, and for how long?’ by Ramzi Ajjan from the University of Leeds in the UK, and colleagues.1 The authors note that cardiovascular disease remains the main cause of mortality in individuals with diabetes mellitus (DM) and also results in significant morbidity. Premature and more aggressive atherosclerotic disease, coupled with an enhanced thrombotic environment, contributes to the high vascular risk in individuals with DM.2 This prothrombotic milieu is due to increased platelet activity together with impaired fibrinolysis secondary to quantitative and qualitative changes in coagulation factors. Yet, management strategies to reduce thrombosis risk remain largely similar in individuals with and without DM. The current review covers the latest in the field of antithrombotic management in DM. The role of primary vascular prevention is discussed together with options for secondary prevention following an ischaemic event in different clinical scenarios including coronary, cerebrovascular, and peripheral artery disease. Antiplatelet therapy combinations as well as combinations of antiplatelet and anticoagulant agents are examined in both the acute phase and long term, including management of individuals with sinus rhythm and those with atrial fibrillation. The difficulties in tailoring therapy according to the variable atherothrombotic risk in different individuals are emphasized, in addition to the varying risk within an individual secondary to DM duration, presence of complications, and predisposition to bleeding events. This review provides the reader with an up to date guide for antithrombotic management of individuals with DM and highlights gaps in knowledge that represent areas for future research, aiming to improve clinical outcome in this high-risk population (Figure 1). Summary of antiplatelet and anticoagulant therapies in individuals with diabetes and vascular disease. ACS, acute coronary syndrome; AF, atrial fibrillation; CAD, coronary artery disease; CVD, cerebrovascular disease; DAPT, dual antiplatelet therapy; NOAC, non-vitamin K oral anticoagulants; PAD, peripheral artery disease; SR, sinus rhythm; VKA, vitamin K antagonist. aDM individuals with damage to ≥1 organ or ≥3 major risk factors, or any risk factor and ≥10-year disease duration without organ damage. bActive bleeding or comorbidities with high bleeding risk. cHistory of intracerebral haemorrhage or ischaemic stroke, history of other intracranial pathology, recent gastrointestinal bleeding or anaemia due to possible gastrointestinal blood loss, other gastrointestinal pathology associated with increased bleeding risk, liver failure, bleeding diathesis or coagulopathy, extreme old age or frailty, or renal failure requiring dialysis or with eGFR <15 mL/min/1.73 m2.dDiffuse multivessel CAD with at least one of the following: diabetes mellitus requiring medication, recurrent MI, PAD, or CKD with eGFR 15–59 mL/min/1.73 m2 (from Ajjan RA, Kietsiriroje N, Badimon L, Vilahur G, Gorog DA, Angiolillo DJ, Russell DR, Rocca B, Storey RF. Antithrombotic therapy in diabetes: which, when, and for how long? See pages 2235–2259). Initially, the use of CKMB (creatine kinase myocardial band) was a major advance in the ability to detect acute myocardial injury because it was more sensitive and specific than other markers that had been applied such as lactate dehydrogenase, serum glutamic oxaloacetic transaminase, and total CK. Originally, it appeared that CKMB activity might be highly specific for injury of myocytes in the myocardium. In a Viewpoint article entitled ‘ESC Study Group on Cardiac Biomarkers of the Association for Acute CardioVascular Care: a fond farewell at the retirement of CKMB’, Allan Jaffe from the Mayo Clinic in Rochester, MN, USA, and colleagues note that transitions in medicine often are difficult, especially when they involve diagnostic methods that are used widely.3 Clinicians may find some of the new tools hard to understand, especially when they are comfortable with the approaches in use. This may particularly be the case with laboratory testing which often has far-reaching consequences. The problems associated with incorporating new testing into clinical paradigms may reflect in part the fact that important elements of the analytics of laboratory testing are less emphasized during medical school and clinical training than they were in the past. In addition, there is a need for closer communication between laboratory professionals and diagnosticians so that the technical and analytical advances in the testing and application of novel biomarkers are better appreciated. The ESC Biomarker Study Group of the Association for Acute CardioVascular Care elaborates further and concludes this contribution with the suggestion that CKMB be eliminated from the menu of biomarkers available for use in the evaluation of patients with cardiovascular disease to be fully replaced by troponins.4,5 In another Viewpoint article entitled ‘Management of antithrombotic therapy in patients undergoing transcatheter aortic valve implantation: a consensus document of the ESC Working Group on Thrombosis and the European Association of Percutaneous Cardiovascular Interventions (EAPCI), in collaboration with the ESC Council on Valvular Heart Disease’, Jurrien ten Berg from the Cardiovascular Research Institute Maastricht (CARIM) in the Netherlands, and colleagues note that transcatheter aortic valve implantation (TAVI) is effective in older patients with symptomatic severe aortic stenosis, while the indication has recently broadened to lower risk and younger patients.6–10 Although thrombo-embolic and bleeding complications after TAVI have decreased over time, such adverse events are still common. The recommendations of the latest 2017 ESC/EACTS Guidelines for the management of valvular heart disease on antithrombotic therapy in patients undergoing TAVI are mostly based on expert opinion.11 Based on recent studies and randomized controlled trials, this Viewpoint document provides updated therapeutic insights into antithrombotic treatment during and after TAVI. Elevated serum levels of C-reactive protein (CRP), a marker of systemic inflammation, are associated with severe disease in bacterial or viral infections. A systemic inflammatory response is observed in coronavirus disease 2019 (COVID-19).12–15 In a clinical research article entitled ‘C-reactive protein and clinical outcomes in patients with COVID-19’, Nathaniel Smilowitz from the New York University School of Medicine in the USA, and colleagues explore associations between CRP concentration at initial hospital presentation and clinical outcomes in patients with COVID-19.16 Consecutive adults aged ≥18 years with COVID-19 admitted to a large New York healthcare system between 1 March and 8 April 2020 were identified. Patients with measurement of CRP were included. Venous thrombo-embolism (VTE), acute kidney injury (AKI), critical illness, and in-hospital mortality were determined for all patients. Among >2700 patients hospitalized with COVID-19, 93% had a CRP measurement (median 108 mg/L). CRP concentrations above the median value were associated with VTE [adjusted odds ratio (aOR) 2.33], AKI (aOR 2.11), critical illness (aOR 2.83), and mortality (aOR 2.59) compared with CRP below the median. A dose response was observed between CRP concentration and adverse outcomes. While the associations between CRP and adverse outcomes were consistent among patients with low and high D-dimer levels, patients with high D-dimer and high CRP had the greatest risk of adverse outcomes (Figure 2). Graphical Abstract (from Smilowitz NR, Kunichoff D, Garshick M, Shah B, Pillinger M, Hochman JS, Berger JS. C-reactive protein and clinical outcomes in patients with COVID-19. See pages 2270–2279). The authors conclude that systemic inflammation, as measured by CRP, is strongly associated with VTE, AKI, critical illness, and mortality in COVID-19. The manuscript is accompanied by an Editorial by Mark Pepys from the Wolfson Drug Discovery Unit in London, UK.17 The author notes that the presence of CRP in the lesions of COVID-19 has not yet been reported but that given the extensive cell damage and the abundance of circulating CRP, it is likely to be present. CRP bound to damaged tissues, injured by the virus and/or by the host response, will activate complement locally, potentially exacerbating the injury as well as contributing to systemic complement activation. Development of a novel small molecule drug that inhibits CRP binding in vivo is currently in progress to test whether this CRP–complement mechanism contributes significantly to severity of COVID-19 and other diseases. In a clinical research article ‘Standardized exercise training is feasible, safe, and effective in pulmonary arterial and chronic thromboembolic pulmonary hypertension: results from a large European multicentre randomized controlled trial’ Ekkehard Grünig from the Heidelberg University Hospital in Germany, and colleagues aimed to evaluate efficacy and safety of exercise training in patients with pulmonary arterial hypertension (PAH) and chronic thrombo-embolic pulmonary hypertension (CTEPH) in a prospective, randomized, controlled, multicentre study.18 For the first time, a specialized PAH/CTEPH rehabilitation programme was implemented in 11 centres across 10 European countries. Out of 129 enrolled patients, 116 patients (58 vs. 58 randomized into a training or usual care control group) on disease-targeted medication completed the study. Patients of the training group performed a standardized in-hospital rehabilitation with mean duration of 25 days [95% confidence interval (CI) 17–33 days], which was continued at home. The primary endpoint, change of 6-min walking distance, significantly improved by 34.1 ± 8.3 m in the training compared with the control group. Exercise training was feasible, safe, and well tolerated. Secondary endpoints showed significant improvements in quality of life, WHO functional class, and peak oxygen consumption compared with the control group. Grünig and colleagues conclude that this is the first multicentre, and so far the largest, randomized, controlled study on feasibility, safety, and efficacy of exercise training as add-on to medical therapy in PAH and CTEPH. Within this study, a standardized specialized training programme with in-hospital start was successfully established in 10 European countries. The article is accompanied by an Editorial by André La Gerche from the Baker Heart and Diabetes Institute in Melbourne, Australia.19 The author highlights that this careful, pragmatic, and well-executed study from 10 different European countries provides a new standard of care with clear evidence that regular exercise training benefits our PAH patients. It reinforces the powerful therapeutic effects that can be measured in addition to best pharmacological care. Rather than continuing to overlook the efficacy of exercise, we should now focus on implementing and improving the delivery of exercise therapies for our patients. Thrombosis is a leading contributor to global disease burden, and one out of four deaths worldwide are caused by thrombosis. Prior studies suggested an inter-relationship between cancer and both arterial thrombo-embolism (ATE) and VTE.20–23 Yet population-based studies on the risk of both ATE and VTE have not been performed. In a clinical research article entitled ‘Relative risk of arterial and venous thromboembolism in persons with cancer vs. persons without cancer: a nationwide analysis’, Ella Grilz from the Medical University of Vienna in Austria, and colleagues looked at this in detail.24 International Classification of Disease 10th Revision (ICD-10) diagnosis codes of all publicly insured persons in Austria were extracted from the Austrian Association of Social Security Providers dataset covering the years 2006–2007. Among almost 160 000 patients with cancer, 5.4% had an ATE diagnosis code and 4.6% a VTE diagnosis code. In contrast, among ∼8 000 000 people without cancer, 0.9% had an ATE diagnosis code and 0.4% a VTE diagnosis code. This corresponds to an age-stratified random-effects relative risk (RR) of 6.88 for ATE and 14.91 for VTE. The proportion of ATE was highest in patients with urinary tract malignancies (RR 7.16) and lowest in patients with endocrine cancer (RR 2.49). The corresponding VTE proportion was highest in cancer of the mesothelium/soft tissue (RR 19.35) and lowest in oropharyngeal cancer (RR 6.62). The authors conclude that the RRs of both ATE and VTE are significantly higher in persons with cancer. Their population-level meta-data indicate a strong association between cancer, ATE, and VTE, and support the concept of shared risk factors and pathobiology between these diseases. The contribution is accompanied by an Editorial by Alexander Cohen from the Guy’s and Saint Thomas’ Hospitals NHS Trust in London, UK and Ingrid Bistervels from the University of Amsterdam in the Netherlands.25 The authors conclude that Grilz and colleagues have shed new light on the relationship between cancer and vascular disease. A more aggressive treatment of classical arterial and venous disease risk factors is required, since outcomes of both ATE and VTE are worse in cancer patients. Risk factor management should be considered for all patients, and prophylaxis should be considered in cancer patients at high risk of thrombosis and low risk of bleeding. Finally, a lower threshold for clinical suspicion and prevention is needed for younger patients with cancer. The issue is complemented by two Discussion Forum articles. In a contribution entitled ‘Because of its association with major bleeding the ADP-binding enzyme creatine kinase should be estimated in studies of patients treated for non-ST-segment elevation acute coronary syndromes (NSTE-ACS)’, Lizzy Brewster from the Amsterdam Institute for Global Health and Development in the Netherlands comments on the recent contribution entitled ‘2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation’ by Jean-Philippe Collet and Holger Thiele and their colleagues from the ESC Scientific Document Group.26,27 Collet and Thiele respond to this contribution in a separate piece.28 The editors hope that readers of this issue of the European Heart Journal will find it of interest. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.