Deeper Anemia Linked to Higher Risk of Bleeding, Stroke in Patients Treated with Warfarin

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Higher risks of bleeding and stroke/transient ischemic attack (TIA) were observed in patients with atrial fibrillation treated with warfarin with deeper anemia, according to a study published in BMJ Open.¹ However, the international normalized ratio (INR) remained at its target and seldomly deviated, therefore failing to detect a complication risk. Suboptimal management and increased complication risk were implied by the repeated low hemoglobin results, which are indicative of persistent anemia.

Current guidelines suggest the use of direct oral anticoagulants (DOACs) to prevent thromboembolic complications in patients with non-valvular atrial fibrillation as there need for routine monitoring using the INR and fewer interactions with other drugs and food. However, warfarin is the only anticoagulant approved for patients with severe mitral stenosis or mechanical heart valve, as well as patients with antiphospholipid antibody syndrome.²

“It is well-known that anemia, as well as other risk factors, such as increased blood pressure, decreased renal function, previous bleeds, smoking, sleep apnea, and concomitant use of antiplatelet agents increase the risk of bleeding in patients using oral anticoagulation,” wrote a group of Finnish investigators. “Anemia also predisposes anticoagulated patients with atrial fibrillation to thromboembolic complications. Hence, hemoglobin, blood cell counts, including red blood cells and platelets, as well as liver and kidney function, need regular follow-up to safely manage anticoagulated patients.”

To determine the frequency of anemia, kidney, and liver function, and the impact on complication risk among a cohort of warfarin-anticoagulated patients, a retrospective nested case-control study was conducted using the national Finnish Warfarin in Atrial Fibrillation (FinWAF) registry. Comprised of 54,568 patients, the registry reported the outcome and management of this patient population. Links between blood count test frequency and results were evaluated together with risk of bleeding or stroke/TIA during a 5-year follow-up period between January 2007 and December 2011.

A total of 9% (n = 4681) of patients reported bleeding and 9% (n = 4692) of patients had stroke/TIA episodes. For those with bleeds, lower hemoglobin (within 3 months) preceded the event when compared with controls (median 126 vs 135 g/L; IQR 111–141 g/L vs 123–147 g/L, P <.001. However, patients with stroke/TIA had only slightly lower INR (median 2.2 vs 2.3; 1.8–2.6 vs 2.1–2.7, P <.001).

When the last measured hemoglobin was below the reference value, which varied between sexes, the odds ratio for a bleeding complication was 2.9 and for stroke/TIA was 1.5. If the level of hemoglobin was below 100 g/L, the complication risk increased by 10-fold. If hemoglobin values were repeatedly low, defined as more than 5 times, during the proceeding 3 months, the future odds ratio for bleeds was 2.3 and 2.4 for stroke/TIA.

Therefore, results indicated severity-dependent anemia and low hemoglobin levels were significant risk factors for stroke/TIA and bleeding in patients with atrial fibrillation treated with warfarin.

Investigators noted the strength of the study was the large number of patients included in the study, which allowed for a nested case-control design with 3 age- and gender-matched controls. However, the retrospective, observational nature of the study and the lack of information on possible interventions after abnormal laboratory results limited the findings.

“Our study highlights the need for earlier, routine testing for blood cell counts to ensure timely diagnosis and treatment of anemia,” investigators concluded. “Our observations are generalizable to the management of warfarin therapy in AF and beyond.”

References

1. ^{Helin TA, Raatikainen P, Lehto M, Haukka J, Lassila R. Associations of anaemia with bleeding and thrombotic complications in patients with atrial fibrillation treated with warfarin: a registry-based nested case-control study. BMJ Open. 2023;13(11):e071342. Published 2023 Nov 2. doi:10.1136/bmjopen-2022-071342}
2. ^{Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European association for cardio-thoracic surgery (EACTS)The task force for the diagnosis and management of atrial fibrillation of the European society of cardiology (ESC) developed with the special contribution of the European heart rhythm association (EHRA) of the ESC. Eur Heart J 2021;42:373–498. doi:10.1093/eurheartj/ehaa612}