Heart failure (HF) is a clinical syndrome caused by a structural or functional disorder of the heart that results in elevated intracardiac pressures and/or inadequate cardiac output during exercise or rest. The condition is associated with an increased risk of both arterial and venous thrombotic events. Greater awareness of the issue among clinicians, as well as more research and clearer guidelines for its management, can support better diagnosis and treatment of coagulation disorders among HF patients.

Pathophysiology of coagulation disorders in HF

HF is divided into 3 subtypes, based on the left ventricular ejection fraction (LVEF): HF with reduced ejection fraction (HFrEF); HF with mildly reduced ejection fraction (HFmrEF); and HF with preserved ejection fraction (HFpEF). Every subtype has specific clinical characteristics and common concomitant diseases, including variable risk of thromboembolic complications [2].

HF and thrombosis are often linked for several reasons. For starters, ischemic heart disease, a leading cause of HF, predisposes to formation of arterial thrombi via platelet activation and aggregation. Venous thromboembolism (VTE) is also common in HF, contributing to elevated risk of cardio embolic stroke and sudden death. The risk of thromboembolism and stroke is particularly high when patients with HF have other comorbid conditions such as atrial fibrillation (AF). More than half of patients with new diagnosis of HF were found to have AF, and the presence of both AF and HF portended a greater mortality risk.

Abnormalities in all three components of Virchow’s triad—endothelial dysfunction, stasis of blood flow, and hypercoagulability—increase the vulnerability to thrombosis in HF. However, aetiologies of arterial and venous thrombosis differ. Arterial clots are platelet-rich and formed under high shear stress, whereas venous clots are fibrin-rich and formed during lower shear stress environments. Regardless of the aetiology of HF or its comorbidities, disruptions in platelet function and its interactions with the coagulation cascade seen in HF promote thrombogenesis [2].

Although thromboembolic complications are not typically recognised as a leading problem in patients with HF, the condition is associated with substantial coagulation disorders [3]. For example, the incidence of stroke is higher in the first month following HF diagnosis or decompensation and decreases within 6 months following the acute event [4]. The prothrombotic phenotype in patients with HF might be due to (1) systemic inflammatory response induced by chronic hypoxia, (2) increased concentrations of prothrombotic molecules, or (3) arterial and venous endothelial dysfunction.

HF was also found to be an independent risk factor for worsened disability, increased hospital readmissions, and higher mortality after stroke. Despite this, no clear guidelines address the role of anticoagulation and antiplatelet therapy in reducing morbidity and mortality associated with coagulation abnormalities in HF [1]. Increased risk of thromboembolic complications in HF thus represents an underappreciated clinical challenge, as HF is characterised by a prothrombotic state that might aggravate its morbidity and mortality.

Clinical management of coagulation disorders in HF

In HF patients, markers of activated coagulation and/or platelet activation have been observed together with endothelial dysfunction and low cardiac output, conditions related to abnormal blood flow and stasis. Moreover, several and commonly observed comorbidities often complicate HF, further increasing the thromboembolic risk.

Thromboembolism prophylaxis by low-molecular-weight heparin is recommended for hospitalised patients with acute HF in the absence of contraindications and in patients treated with long-term mechanical circulatory support [1]. In the past decade, direct oral anticoagulants (DOACs) have also been approved for the treatment and prevention of stroke and systemic embolism (SSE) in non valvular AF. These drugs are an alternative to warfarin with a lower risk of bleeding [3].

Anticoagulation in patients with AF and HF is widely considered essential to reduce the high thromboembolic risk in these patients. ESC guidelines recommend the use of DOACs rather than Warfarin to prevent stroke in AF, since these drugs are similarly effective with a safer clinical profile However, HF patients are under-represented in randomised controlled trials [3].

In HF patients with AF, DOACs like Apixaban and Dabigatran (but not Rivaroxaban) were associated with a lower risk of total bleeding and death than Warfarin at all levels of renal function. Although DOAC treatment is considerably less complex than Warfarin, their use in patients with HF is not a set-and-forget matter. Renal function fluctuated commonly in patients with HF, sometimes requiring DOAC dosage adjustment, yet these adjustments were infrequent in practice. Even modest declines in renal function were associated with increased bleeding risk in DOAC-treated patients, emphasising the need for careful monitoring and adjusting doses appropriately.

Specialist care in anticoagulation clinics or by clinical pharmacists is associated with improved DOAC dose-adjustments and outcomes. Further study of the observed variations in performance between sites may provide an opportunity to further improve the quality of care for DOAC-treated patients [4].

The need for further research

With a worldwide prevalence of 1%-2%, HF represents a major global disease that is projected to affect more than 8 million adults, and total HF related costs are estimated to increase to $70 billion by 2030. Despite recent evidence-based advances in medical management of HF, such as incorporation of implantable cardiac defibrillators and cardiac resynchronisation therapy, mortality associated with HF remains high at approximately 50% at 5 years.

Given that HF patients are exposed to a high thromboembolic risk, especially in the presence of AF, DOAC treatment seems a reasonable approach to reduce the risk of thromboembolic events with a good safety profile. However, due to the lack of specific data, clinical decisions are currently adapted from evidence of large RCTs in the general AF population.

Several important questions remain unsolved in the use of DOACs in HF and need further in depth analysis. Do DOACs affect specific HF endpoints, such as HF worsening or hospitalisations? How should we manage anticoagulation in HF-AF patients with comorbidities? How should we combine antiplatelets and anticoagulants in HF-AF-CAD patients? Can we safely and effectively use DOACs in HFAF patients with LV thrombi? When should we start DOAC therapy in HF patients with an increased risk of both LV thrombi and AF?

HF represents a unique clinical setting that requires targeted clinical studies and a tailored therapy to limit adverse events. Such studies would help define the clinical decision of DOAC choice in the vast group of HF patients and in the single different clinical scenarios. [3]

*DOACs: The 2023 ISTH SSC recommends to describe anticoagulant medications by their mode of administration and specific target (e.g., oral factor Xia inhibitor, parenteral factor XIIa inhibitor). (5)

References:
[1] SINIARSKI, A. et al. (2023) ‘Blood coagulation disorders in heart failure: From basic science to clinical perspectives’, Journal of Cardiac Failure, 29(4), pp. 517–526. doi:10.1016/j.cardfail.2022.12.012.

[2] Kim, J.H. et al. (2016) ‘Coagulation abnormalities in heart failure: Pathophysiology and therapeutic implications’, Current Heart Failure Reports, 13(6), pp. 319–328. doi:10.1007/s11897-016-0308-6.

[3] Paolillo, S. et al. (2020) ‘Direct oral anticoagulants across the heart failure spectrum: The Precision Medicine Era’, Heart Failure Reviews, 27(1), pp. 135–145. doi:10.1007/s10741-020-09994-0.

[4] Jackevicius, C.A. et al. (2021) ‘Bleeding risk of direct oral anticoagulants in patients with heart failure and atrial fibrillation’, Circulation: Cardiovascular Quality and Outcomes, 14(2). doi:10.1161/circoutcomes.120.007230.

[5] Barnes, G.D. et al. (2023) ‘Recommendation on the nomenclature for anticoagulants: Updated communication from the International Society on Thrombosis and Haemostasis Scientific and standardization commitee on the control of anticoagulation’, Journal of Thrombosis and Haemostasis, 21(5), pp. 1381–1384. doi:10.1016/j.jtha.2023.02.008.