Antithrombotic Treatment: How to Navigate Between the Scylla of Thrombosis and the Charybdis of Bleeding?

Filippo Crea


Eur Heart J. 2022;43(37):3499-3502. 

This Focus Issue on thrombosis and antithrombotic treatment contains a Debate entitled 'Great Debate: triple antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting should be limited to 1 week'.[1] Raffaele De Caterina from the Pisa University Hospital in Italy provides an introduction. Subsequently Renato Lopes from Duke University Medical Center in Durham, NC (USA) and colleagues, and Mattia Galli from the Catholic University of the Sacred Heart in Rome, Italy and colleagues, supply pros and contras, respectively, on the statement written in the title. All guideline and consensus documents have emphasized the need for tailoring duration of triple therapy to the individual patient, but the issue of where to put the bar for a 'standard' duration, the 'default duration', is of relevance, as most cardiologists will take this as the reference for most of their patients. Here, therefore, two groups of authors argue one way or the other, defending or opposing the default 1 week duration of triple antithrombotic therapy after stenting for an acute coronary syndrome (ACS) with atrial fibrillation.[2,3] The reader should thus see the pros and contras of the two different positions, as well as the intermediate grey between them in the difficult practice of this 'precision medicine'. Understanding the background of both opinions will allow a proper handling of the quite diverse situations encountered in such a difficult navigation between the Scylla of thrombosis and the Charybdis of bleeding (Figure 1).

Figure 1.

Key points in favour or against the use of 1-week triple antithrombotic therapy for the majority of patients with AF and ACS/PCI. Abbreviations: TT, triple antithrombotic therapy; OAC, oral anticoagulant; DAPT, dual antiplatelet therapy; RCT, randomized controlled trials; ACS, acute coronary syndrome; PCI, percutaneous coronary intervention.1

It is well recognized that atrial fibrillation (AF) is an important risk factor for stroke.[4–8] There is currently no consensus, however, on whether atrial fibrillation (AF) patients at low risk for stroke (one non-sex-related CHA2DS2-VASc point) should be treated with an oral anticoagulant.[9] In a Clinical Research article entitled 'Oral anticoagulants in patients with atrial fibrillation at low stroke risk: a multicentre observational study' Joris Komen from Utrecht University in The Netherlands and colleagues conducted a multi-country cohort study in Sweden, Denmark, Norway, and Scotland.[10] In total, 59 076 patients diagnosed with AF at low stroke risk were included. The authors assessed the rates of stroke or major bleeding during treatment with a non-vitamin K antagonist oral anticoagulant (NOAC), a vitamin K antagonist (VKA), or no treatment, using inverse probability of treatment weighted Cox regression. In untreated patients, the rate for ischaemic stroke was 0.70 per 100 person-years and the rate for a bleed was also 0.70 per 100 person-years. Comparing NOAC with no treatment, the stroke rate was significantly lower [hazard ratio (HR) 0.72], and the rate for intracranial haemorrhage (ICH) was not increased (HR 0.84). Comparing VKA with no treatment, the rate for stroke tended to be lower (HR 0.81), and the rate for ICH tended to be higher during VKA treatment (HR 1.37). Comparing NOAC with VKA treatment, the rate for stroke was similar (HR 0.92), but the rate for ICH was significantly lower during NOAC treatment (HR 0.63).

Komen and colleagues conclude that these observational data suggest that NOAC treatment may be associated with a positive net clinical benefit compared with no treatment or VKA treatment in patients with AF at low stroke risk, a question that can be tested through a randomized controlled trial. The contribution is accompanied by an Editorial by William McIntyre from McMaster University in Hamilton, Ontario (Canada), and Dominik Linz from the Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht in The Netherlands.[11] The Editorialists suggest that there is a role for randomized clinical trials to address patients with AF who are at perceived low risk of stroke. Whereas these trials will allow us to rigorously estimate treatment effects, they are not the only missing piece of the puzzle. Continued epidemiological work is needed to help us understand the baseline stroke risks of the different types of patients with AF who currently do not qualify for OAC based on their CHA2DS2-VASc score. Patient-centred studies and economic analyses will also help us create a quantitative concept of what we currently consider to be qualitatively 'low risk' in the large population of AF patients.

The combination of aspirin and rivaroxaban may offer a clinical benefit versus aspirin alone in patients with atherosclerotic cardiovascular disease.[12] In a Clinical Research article entitled 'Rivaroxaban and aspirin vs. aspirin alone in Asian compared with non-Asian patients with chronic coronary artery disease or peripheral arterial disease: the COMPASS trial', Masatsugu Hori from the Osaka International Cancer Institute in Japan and colleagues point out that it is unknown whether Asian and non-Asian patients with atherosclerotic vascular disease derive similar benefits from long-term antithrombotic therapy.[13] In patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies trial, the effects of rivaroxaban 2.5 mg b.i.d. plus aspirin 100 mg o.d. were compared with those of aspirin 100 mg o.d. in Asian vs. non-Asian patients (race was self-identified). Asians (n = 4269) vs. non-Asians (n = 23 126) had similar rates of major adverse cardiovascular events (MACEs) (4.85% vs. 4.83%, P = 0.30) and modified International Society on Thrombosis and Haemostasis (ISTH) major bleeding (2.72% vs. 2.58%, P = 0.22), but higher rates of ICH (0.63% vs. 0.29%, P = 0.01) and minor bleeding (13.61% vs. 6.49%, P < 0.001). In Asians vs. non-Asians, the combination of rivaroxaban and aspirin compared with aspirin alone produced significant and similar reductions in MACEs (Asians: HR: 0.64; non-Asians: HR: 0.78), and significant and similar increases in modified ISTH major bleeding (Asians: HR 2.24; non-Asians: HR: 1.60) while the increase of ICH was higher in Asians (Asians: HR: 3.50; non-Asians: HR: 0.81; P for interaction = 0.04) (Figure 2).

Figure 2.

Incidence rates and effects of rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily compared with aspirin 100 mg once daily on efficacy, safety, and net clinical outcome in Asian compared with non-Asian patients.13

The authors conclude that Asian compared with non-Asian patients with chronic CAD and/or PAD have higher rates of ICH and minor bleeding. The combination of rivaroxaban and aspirin vs. aspirin alone produces similar effects for MACE and modified ISTH major bleeding, whereas they are associated with higher rates of ICH in Asian patients. The contribution is accompanied by an Editorial by Shinya Goto and Shinichi Goto from the Tokai University School of Medicine in Isehara, Japan.[14] The authors conclude that Hori et al. provided important data regarding overall homogeneity, with little heterogeneity, between Asian and non-Asian from the large, credible cohort of the COMPASS trial. Further investigation such as cardiovascular and bleeding events in Asians living in Asian countries vs. Asians living in non-Asian countries with a huge international database is needed.

The price to pay for antithrombotic treatment is an increase of the bleeding risk.[15–18] Galectin-3, a β-galactoside-binding lectin, is abnormally increased in cardiovascular disease. The direct effects of Galectin-3 on platelet activation remain unclear. In a Translational Research article entitled 'Galectin 3 enhances platelet aggregation and thrombosis via Dectin-1 activation: a translational study', Yufei Chen from the Shanghai University of Traditional Chinese Medicine in China and colleagues explore the direct effects of Galectin-3 on platelet activation and thrombosis.[19] A strong positive correlation between plasma Galectin-3 concentration and platelet aggregation or whole blood thrombus formation was observed in patients with coronary artery disease (CAD). Multiple platelet function studies demonstrated that Galectin-3 directly potentiated platelet activation and in vivo thrombosis. Mechanistic studies using the Dectin-1 inhibitor, laminarin, and Dectin-1−/− mice revealed that Galectin-3 bound to and activated Dectin-1, a receptor not previously reported in platelets, to phosphorylate spleen tyrosine kinase and thus increased Ca2+ influx, protein kinase C activation, and reactive oxygen species production to regulate platelet hyper-reactivity. TD139, a Galectin-3 inhibitor in a Phase II clinical trial, concentration dependently suppressed Galectin-3-potentiated platelet activation and inhibited occlusive thrombosis without exacerbating haemorrhage in ApoE−/− mice, which spontaneously developed increased plasma Galectin-3 levels. TD139 also suppressed microvascular thrombosis to protect the heart from myocardial ischaemia–reperfusion injury in ApoE−/− mice.

Chen et al. conclude that Galectin-3 is a novel positive regulator of platelet hyper-reactivity and thrombus formation in CAD. As TD139 has potent antithrombotic effects without bleeding risk, Galectin-3 inhibitors may have therapeutic advantages as potential antiplatelet drugs for patients with high plasma Galectin-3 levels. This manuscript is accompanied by an Editorial by Kai Jakobs and Ursula Rauch from the Campus Benjamin Franklin Charité–Universitätsmedizin Berlin in Germany.[20] Jakobs and Rauch conclude that further in-depth research is necessary to explore the molecular mechanisms that underlie Galectin-3 involvement in cardiovascular disease progression. Despite all the unpredictability associated with drug development, it is only rational to expect that—upon availability of more advanced Galectin-3 inhibitors—clinical researchers will soon start to study whether Galectin-3 inhibition is effective to improve the clinical prognosis in patients after ACS.

Big data are central to new developments in global clinical science aiming to improve the lives of patients. Technological advances have led to the routine use of structured electronic healthcare records with the potential to address key gaps in clinical evidence. In a Special Article entitled 'CODE-EHR best practice framework for the use of structured electronic healthcare records in clinical research', Dipak Kotecha from the University of Birmingham in the UK, and colleagues point out that the Covid-19 pandemic has demonstrated the potential of big data and related analytics, but also important pitfalls.[21] Verification, validation, and data privacy, as well as the social mandate to undertake research, are key challenges. The European Society of Cardiology and the BigData@Heart consortium have brought together a range of international stakeholders, including patient representatives, clinicians, scientists, regulators, journal editors, and industry. This Special Article proposes the CODE-EHR Minimum Standards Framework to improve the design of studies, enhance transparency, and develop a roadmap towards more robust and effective utilization of healthcare data for research purposes.

Finally, the issue concludes with a Viewpoint 'Challenges of diversity and inclusion and the need for change' by Estefania Oliveros from Temple University Hospital in Philadelphia, PA (USA) and colleagues.[22] The authors highlight that there is a scant representation of members of under-represented minorities along the journey from medical school to cardiology. The consequence may indeed be poor health outcomes in at-risk communities. They conclude that increasing diversity within the field of medicine is a path towards excellence. Improved patient care, reduced healthcare disparities, and elimination of conscious and unconscious biases are the laudable goals. The final questions for personal and professional reflection are the following. Is this right? Is this just? Is diversity a priority? The answers will determine our future.

The editors hope that this issue of the European Heart Journal will find the interest of its readers.

Dr. Crea reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work.