The search for the holy grail: the balance between the risk of thrombosis and bleeding in patients

The balance between bleeding and cardiovascular events by dual antiplatelet treatment (DAPT) is a critical concern in patients undergoing percutaneous coronary intervention (PCI). De-escalation and shortening of the (DAPT) after an acute coronary syndrome (ACS) event has during the last years, been discussed in several publications.1–7 The STOPDAPT-3 (ShorT and OPtimal Duration of Dual AntiPlatelet Therapy-3) trial aimed to compare the aspirin free strategy with DAPT after PCI in terms of the major bleeding and cardiovascular events. The no-aspirin strategy compared to the DAPT strategy failed to reduce major bleeding within 1 month after PCI. Moreover, there was a signal suggesting an excess of coronary events in the no-aspirin group relative to the DAPT group. The excess risk of the no-aspirin group relative to the DAPT group for coronary events was more prominent in patients with ACS than in those with non-ACS.8 In this issue of the journal, Dr Kimura and co-workers from Japan present the pre-specified subgroup analyses based on high bleeding risk (HBR) in 4476 ACS patients enrolled in STOPDAPT-3. The authors concluded that the no-aspirin strategy compared to the DAPT strategy failed to reduce major bleeding events irrespective of HBR and ACS subtypes. Since the 1990s, Glycoprotein IIb/IIIa inhibitors (GPI) have been used widely in the management of ACS patients to prevent thrombosis related events.9 However, most studies assessing the safety and effectiveness of these drugs were conducted prior to the introduction of potent P2Y12 inhibitors, which drastically changed the treatment of ACS patients and led to a sharp decline in the use of GPI.10 Dr Lüscher et al., aimed to assess the utilization, effectiveness, and safety of GPI in a prospective multi-centre cohort of contemporary 4395 ACS patients. The study group observed a reduced risk of (major adverse cardiovascular events) MACE and an increased risk of major bleedings during a year in patients treated with GPI and concluded that GPI might be considered in selected patients following a personalized balancing between ischaemic and bleeding risks. Phosphodiesterase 5 inhibitors are widely used for the treatment of erectile dysfunction (ED) and also have systemic vascular effects. Their mechanism of action works by selectively inhibiting the degradation of cGMP signaling in vascular smooth muscle cells, thereby enhancing nitric-oxide availability which promotes vascular dilatation.11 Dr Vlachopoulos and colleagues from Greece, aimed to evaluate the effects of PDE5i on long-term cardiovascular outcomes and mortality in a comprehensive search of electronic databases. Cohort studies comparing PDE5i treatment at any dose with other ED treatment, placebo or no treatment and minimum follow-up duration of 6 months were considered eligible. Sixteen studies were included (1 257 759 subjects—10.5% treated with PDE5i). The authors reported that the use of PDE5i primarily in men with or without known coronary artery disease was associated with a lower risk for cardiovascular events and overall mortality. Out-of-hospital cardiac arrest (OHCA) accounts for 50% of all cardiovascular deaths.12 A known mechanism by which drugs increase the risk of OHCA is by blocking cardiac potassium channels, thereby impairing cardiac repolarization and prolonging the QT-interval on the electrocardiogram, potentially leading to Torsade de Pointes arrhythmia.13 PPIs may be associated with increased risk of cardiovascular mortality and comorbidity.14,15 Dr Eroglu and co-workers identified 46 578 OHCA-cases and 232 890 matched non-OHCA-controls. PPI was used by 8769 OHCA-cases and 21 898 non-OHCA-controls, and current use of PPI was associated with increased odds of OHCA compared with non-users while past use conferred no increase in the odds of OHCA. A comment on the study is made by Dr Tsiartas. Different doses and length of edoxaban treatment have been examined in conditions as atrial fibrillation and cancer.16–18 Cancer-associated isolated distal deep vein thrombosis (DVT) is reported to account for 11% of all cancer-associated thromboses and negatively impacts the prognosis in cancer patients.16,19 A randomized clinical trial (RCT), the ONCO DVT study, showed the potential benefit of an extended anticoagulation therapy with edoxaban for patients with cancer-associated isolated distal DVT in terms of the thrombotic risk.19 In a pre-specified subgroup analysis of the ONCO DVT study.20 Dr Yamashita and colleagues from Japan, stratified the patients into those with a standard edoxaban dose (60 mg/day) and those with a reduced edoxaban dose (30 mg/day) and evaluated the clinical outcomes for the 12-month and 3-month treatments. They reported that a 12-month edoxaban regimen for cancer-associated isolated distal DVT was consistently superior to a 3-month regimen, across the edoxaban doses for the thrombotic risk. However the 12-month cumulative incidence of major bleeding was higher in the 12-month group than 3-month group for the 60 mg edoxaban subgroup. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have a central role in cardiovascular and renal risk reduction among patients with type 2 diabetes and among patients with heart failure.21–25 Empagliflozin and dapagliflozin are the most frequently prescribed SGLT2 inhibitors worldwide. Engström and co-workers from Sweden, aimed to compare cardiovascular and renal effectiveness and safety of empagliflozin vs. dapagliflozin using nationwide data from routine clinical practice in Sweden, Denmark, and Norway, including 141 065 new users of empagliflozin and 58 306 new users of dapagliflozin. The conclusion of the study was that use of empagliflozin and dapagliflozin was associated with similar risk of cardiovascular and renal outcomes, mortality, and diabetic ketoacidosis. Left ventricular thrombus (LVT) may develop due to severe deterioration of left ventricular systolic function. LVTs are typically found in areas of regional akinesia that promote stasis of blood and clot formation. In recent years, direct oral anticoagulants (DOACs) have replaced vitamin K antagonists (VKAs) in many clinical indications,17,26–29 but dedicated trials in patients with LVT are scarce. Dr Haller and co-workers carried out a systematic meta-analysis comparing results in the available literature regarding DOAC vs. VKA therapy in patients with LVT, and providing pooled effect estimates for efficacy and safety endpoints. They identified 22 articles (18 observational studies, 4 small RCTs) reporting on a total of 3587 patients (2489 VKA vs. 1098 DOAC therapy). The authors concluded that the use of DOACs in patients with LVT was not associated with a significant difference in stroke or systemic embolism, or thrombus resolution compared to VKA therapy. The use of DOACs was associated with a lower rate of all-cause death and fewer bleeding events. Aortic stenosis (AS) is a common valvular heart disorder in developed countries. The European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines for the management of valvular heart disease recommend TAVI in patients aged ≥75 years or those who are at high risk or unsuitable for surgery.30 The optimal antithrombotic therapy to balance the risk of thrombosis and bleeding in patients who undergo transcatheter aortic valve implantation (TAVI) is unknown.31 Dr Arden and colleagues performed a meta-analysis of RCTs aimed to evaluate the efficacy and safety of different oral anticoagulant (OAC) and antiplatelet regimens in patients post-TAVI. The authors included 11 RCTs (n = 6415). The combination of OAC plus single antiplatelet therapy (SAPT) increased the risk of all-cause death compared with DAPT (OR 1.78, 95% credible interval 1.15–2.77). No other comparisons for all-cause death were significantly different. For major bleeding, SAPT reduced the risk compared with DAPT, direct-acting OAC, and OAC + SAPT (OR 0.20–0.40), and DAPT reduced the risk compared with OAC + SAPT. SAPT and DAPT ranked best for all-cause death, while SAPT ranked best for major bleeding. The conclusion of the study group was that in post-TAVI patients, SAPT may provide the optimal balance of reducing thrombotic events while minimizing the risk of bleeding. Glycoprotein (GP) VI plays a major role in thrombosis but not haemostasis, making it a promising antithrombotic target.32 In a review paper, DR Slater and co-workers, summarize mechanisms of GPVI activation and the latest progress of clinically tested GPVI inhibitors, including their mechanisms of action. By focusing on what is known about GPVI activation.