The year in cardiovascular medicine 2023: the top 10 papers in thrombosis and antithrombotic treatment (2024)

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Preventing thrombosis while minimizing bleeding is paramount in antithrombotic therapy. Recent progress has brought this goal closer. This Viewpoint highlights recent pivotal papers on antithrombotic strategies, with findings summarized in the Graphical Abstract.

Acute or chronic coronary syndromes

The direct thrombin inhibitor bivalirudin is considered safer than unfractionated heparin (UFH) but limited by a higher incidence of early stent thrombosis.¹ As this may be due to bivalirudin’s short half-life, prolonged infusion after percutaneous coronary intervention (PCI) might mitigate stent thrombosis without excessive bleeding. In the Bivalirudin With Prolonged Full-Dose Infusion During Primary PCI Versus Heparin Trial (BRIGHT)-4, 6016 Chinese patients with ST-segment elevation myocardial infarction (MI) received bivalirudin with a 2–4 h infusion post-PCI or a UFH bolus.² At 30 days, bivalirudin outperformed UFH in the primary outcome of Bleeding Academic Research Consortium (BARC) 3–5 bleeds and all-cause mortality (3.1% vs. 4.4%, P = .007). Any death, stent thrombosis, and BARC 3–5 bleeds consistently favoured bivalirudin (although unadjusted for multiple comparisons). Limitations included higher tirofiban use in the UFH group, rare occurrence of major bleeding (0.2% vs. 0.8%), and stent thromboses occurring mostly beyond the first day, making attribution to the presence or absence of bivalirudin challenging.

The net benefit of potent P2Y12-inhibitors over clopidogrel, on a background of aspirin, may be most pronounced in acute coronary syndrome (ACS) patients who hyporespond to clopidogrel. Therefore, platelet-function testing or genotyping to identify clopidogrel hyporesponders might optimize P2Y12-inhibitor choice and patient outcomes. A network meta-analysis of randomized controlled trials (RCTs) involving 61 898 ACS patients, comparing any P2Y12-inhibitor as well as standard vs. guided P2Y12-inhibitor selection,³ suggests that guided P2Y12-inhibitor choice can reduce major adverse cardiovascular events (MACE) without clearly increasing bleeding compared to unguided clopidogrel use.⁴ The relative value of genotyping vs. platelet-function testing or of P2Y12-inhibitor escalation vs. de-escalation remains uncertain.⁴ A guided approach may also be relevant for patients receiving clopidogrel monotherapy, although this strategy has not yet been studied.

The optimal duration of dual antiplatelet therapy (DAPT) post-PCI in high-bleeding risk (HBR) patients remains unclear. An 11-RCT meta-analysis, involving 9006 HBR patients without indication for oral anticoagulation (OAC) and undergoing PCI for acute (58%) or chronic coronary syndrome (CCS, 42%), showed that 1–3 month vs. standard 6–12 month DAPT reduced major or clinically relevant non-major bleeding [risk ratio (RR) 0.76, 95% confidence interval (CI) 0.61–0.94], major bleeding (RR 0.80, 95%CI 0.64–0.99), and cardiovascular mortality (RR 0.79, 95%CI 0.65–0.95).⁵ All-cause death, MACE, MI, or stent thrombosis rates did not differ significantly by DAPT duration. The results appeared independent of ACS or CCS presentation and of HBR criteria (Academic Research Consortium or PRECISE-DAPT). Thus, abbreviated DAPT post-PCI appears to be a safe option for HBR patients.

Clopidogrel may be a valid alternative to aspirin post-PCI. Among 4717 Korean patients, randomized within the HOST-EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Extended Antiplatelet Monotherapy) trial to clopidogrel or aspirin monotherapy for 24 months starting 6–18 months after uneventful PCI, a post-trial follow-up extension to 5.8 years recorded a lower composite rate of all-cause death, nonfatal MI, stroke, ACS-readmission, and BARC ≥3 bleeds (12.8% vs. 16.9%, P < .001). Treatment discontinuation and risks of thrombotic outcomes, gastrointestinal or BARC ≥2, or intracranial bleeds were each significantly lower among clopidogrel users vs. aspirin users. All-cause death did not differ significantly (6.2% vs. 6.0%, P = .72).⁶ Despite some limitations [open-label (but blinded adjudication) design and post-trial per-protocol analysis], the findings suggest that, in stabilized patients post-PCI, clopidogrel is at least as safe and effective as aspirin for long-term monotherapy.

Atrial fibrillation (AF) or device-detected atrial arrhythmias

Coagulation factor (F)XI is believed to be important in thrombus amplification, but less so in thrombogenesis. FXI/XIa-inhibitors may thus preserve primary haemostasis while preventing thrombus growth.⁷ Phase 2 RCTs of some of these agents have revealed efficacy in preventing venous thromboembolism after orthopaedic surgery, with less bleeding compared to enoxaparin.⁷ This year, the phase 2 AZALEA-TIMI 71 trial (A Multicenter, RandomiZed, Active-ControLled Study to Evaluate the Safety and Tolerability of Two Blinded Doses of Abelacimab Compared With Open-Label Rivaroxaban in Patients With Atrial Fibrillation), comparing the subcutaneous monoclonal anti-FXI antibody abelacimab to rivaroxaban in moderate-to-high risk AF patients, was stopped early for overwhelming reduction in bleeding (Ruff CT et al. Circulation 2023 abstract). The study was not powered to assess thrombotic events. On the other hand, the phase 3 OCEANIC-AF trial [A Study to Learn How Well the Study Treatment Asundexian Works and How Safe it is Compared to Apixaban to Prevent Stroke or Systemic Embolism in People With Irregular and Often Rapid Heartbeat (AF)], comparing the oral FXIa-inhibitor asundexian to apixaban in AF patients, was also stopped prematurely for cited lack of efficacy (https://www.bayer.com/media/en-us/oceanic-af-study-stopped-early-due-to-lack-of-efficacy/). Whether the latter reflects inadequate asundexian dosing and whether similar concerns will emerge for other FXI/XIa-inhibitors against active comparators remains unknown.

Patients with clinical AF and a low-stroke risk are under-represented in RCTs of OAC for stroke prevention. Thus, societal guidelines differ in recommending OAC to AF patients with Congestive heart failure, Hypertension, Age ≥65 or 75, Diabetes, Stroke, and VAscular disease-scores (CHADSVA) ≤1.⁸ Among 59 076 Northern European AF patients with low-stroke risk, the rates of stroke or major bleeding were compared for those treated with a vitamin K antagonist (VKA), a direct oral anti-FXa or anti-FIIa (DOAC), or no treatment, using inverse probability treatment weighted Cox regression.⁹ Although one cannot exclude residual confounding, compared to no anticoagulant, DOAC use was associated with lower stroke risks without excessive intracranial haemorrhages (ICH), whereas VKA was associated with a trend towards lower stroke, but increased ICH, rates.⁹ Another analysis of >1 million Norwegians with CHADSVA ≤1 reported higher stroke rates in persons with AF, compared to the general population with a similar risk profile, when not anticoagulated.¹⁰ OAC use was also associated with overall favourable clinical outcomes.¹⁰ These observational studies support the concept that DOAC use may offer net clinical benefit to persons with clinical AF at low stroke risk, but RCTs are required to definitively address the question.

For CHADSVA ≥2, the risk-benefit ratio of OAC in the setting of subclinical (device-detected) atrial high-rate episodes (AHRE) or subclinical AF (SCAF) lasting <24 h is unclear. The double-blind Apixaban for the Reduction of Thrombo-Embolism in Patients with Device-Detected Subclinical Atrial Fibrillation (ARTESIA) trial randomized 4012 patients with SCAF lasting from 6 min to 24 h and a CHADSVA ≥2 (mean age 77 years) to full-dose apixaban or aspirin 81 mg daily.¹¹ After a mean of 3.5 years, the primary efficacy outcome of stroke or systemic embolism (SSE) occurred in 0.78% patient-years with apixaban vs. 1.24% patient-years with aspirin (P = .007). Major bleeding according to International Society on Thrombosis and Haemostasis (ISTH) criteria occurred in 1.71% of patient-years with apixaban vs. 0.94% patient-years with aspirin (P = .001), without a significant difference in fatal bleeds. In another double-blind trial [the Non-Vitamin K Antagonist Oral Anticoagulants in Patients with AHRE-Atrial Fibrillation Network (NOAH-AFNET 6)], 2536 patients with device-detected AHRE lasting at least 6 min were randomized to full-dose edoxaban or placebo.¹² Eligible persons were ≥65 years old (mean 78 years) and had an additional CHADSVA factor (median CHADSVA 3). Those randomized to placebo received aspirin in 54%. The trial was stopped early (median 21-month follow-up) for safety concerns (all-cause death or ISTH-major bleeding, 5.9% vs. 4.5%, P = .03) and for informally assessed lack of efficacy, defined by cardiovascular death or SSE (3.2% vs. 4.0%, P = .15). Stroke rates were 1% patient-years in both arms. Although ARTESIA and NOAH-AFNET 6 differ in sample size, trial duration, type of DOAC, aspirin use in the comparator arm, and safety and efficacy definitions, they suggest that, regardless of CHADSVA ≥2 and older age, the absolute stroke risk associated with SCAF or AHRE is relatively low and the net benefit from full-dose OAC over aspirin or placebo may be slim. Patient-level analyses of hom*ogeneous outcomes from these two trials may help future clinical decision-making.

Acute ischaemic stroke or transcatheter aortic valve implantation (TAVI)

Among 628 stroke patients with large-vessel occlusion in the anterior intracranial circulation and a National Institutes of Health Stroke Scale score (NIHSS) ≥ 2 undergoing endovascular treatment within 6 h of symptom onset, the open-label Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN-MED) compared the effects of 300-mg intravenous (IV) aspirin, moderate- or low-dose UFH, both, or neither on the 90-day modified Rankin scores and on rates of symptomatic ICH.¹³ Median age was 73 years, NIHSS 15, and time from symptom onset 143 min. Outcomes were adjusted for baseline prognostic variables. The trial was stopped early for safety concerns, as aspirin and UFH, compared to none, were each associated with increased risks of symptomatic ICH (14% vs. 7% and 13% vs. 7%, respectively) and a trend towards worse modified Rankin scores. Despite some limitations (e.g. non-exclusion of IV thrombolytics, given to 74%, and early trial-discontinuation), the findings discourage routine IV periprocedural aspirin or UFH during endovascular stroke treatment at the investigated doses in such patients.

Optimal antithrombotic therapy in patients undergoing transcatheter aortic valve implantation (TAVI) with or without a concomitant indication for OAC was investigated in the open-label Anti-Thrombotic Strategy to Lower All Cardiovascular and Neurologic Ischemic and Hemorrhagic Events after TAVI for Aortic Stenosis (ATLANTIS) trial, that randomized 1500 patients, stratified by baseline indication for OAC, to full-dose apixaban or standard antithrombotic care.¹⁴ Mean age was 82 years. In the whole population, at 1 year, the composite primary endpoint of death, MI, SSE, transient ischaemic attack, deep vein thrombosis, cardiac or prosthetic-valve thrombosis, pulmonary embolism, and ISTH-major bleeds did not differ significantly between treatment arms (noninferiority was met, but not superiority).¹⁴ Valve thrombosis was lower with apixaban. However, in patients with no clear OAC indication, all-cause mortality was significantly higher with apixaban vs. standard care (that did not include OAC). The findings suggest that apixaban may be used instead of VKA in TAVI patients with a clear OAC indication, but not (as for other OAC) in the absence of a clear OAC indication.^14,15

Declarations

Disclosure of Interest

F.A. reports receiving speaker or consultancy fees from Amgen, AstraZeneca, Bayer, BMS/Pfizer, DaiichiSankyo, and Servier. M.L.O’D. reports grants, via Brigham and Women’s Hospital, from Novartis, Amgen, AstraZeneca, Janssen and honoraria from Novartis, Amgen, Janssen and Novo Nordisk. J.M.T.B. reports institutional grants from ZonMw (Dutch government), AstraZeneca, Daichi Sankyo, Medtronic and receiving speaker or consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Meyer Squibb, Daiichi Sankyo, Ferrer, Pfizer, and Celecor.

References

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