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of contraindications to warfarin therapy. INR = international normalization ratio.

      Source: Horstkotte et al.,⁴⁹ ©1993, ICR Publishers.

There is no biomarker that reflects direct anticoagulant biological activity. Fixed doses are given, although, based on studies conducted so far, it is advisable to adjust the dose in different situations, as mentioned above.

      Age‐related factors that predispose to bleeding

      Tissue modifications

      Any bleeding, even if it seems spontaneous, has an anatomical explanation: sometimes as the result of atrophy that occurs with age (which favours skin hematomas), but other times due to injuries (including malignant) in the bladder or bowel that appear earlier than in patients not receiving anticoagulation therapy. All patients who bleed should be investigated for underlying pathology, even if the bleeding episode occurred when the INR was excessive. Clinicians should also consider the possibility of occult bleeding in any patient with unexplained symptoms or signs while receiving anticoagulation.

      Falls

      One of the most frequently cited reasons for nontreatment is the perception of a high risk of falls and associated concerns about bleeding, especially intracranial haemorrhage.⁵¹ The study of Man‐Son‐Hing, et al. estimated that an individual would have to fall 295 times in one year for the risk of fall‐related major bleeding to outweigh the benefit of warfarin in reducing the risk of stroke.⁵² So, based on available evidence, perception of a high risk of falling should not be taken as justification not to initiate or to withhold anticoagulation in older patients who are otherwise suitable candidates for such therapy.⁴⁸

      Concomitant use of antiplatelets

      30% of patients with NVAF who receive treatment with anticoagulants as primary stroke prevention receive antiplatelet agents concomitantly, with the risk of bleeding that this implies. The concomitant use of DOACs with antiplatelet agents has shown a decrease in the incidence of intracranial bleeding and other major bleeds but similar incidence of gastrointestinal bleeding when compared with VKAs and antiplatelets.⁵³

      Duration of anticoagulant therapy

      Stroke prevention in NVAF or prevention of thromboembolism from a prosthetic heart valve requires long‐term anticoagulation, and many elderly patients are prescribed anticoagulants for these reasons. Although data on the risk of VTE recurrence in elderly subjects are controversial, the risk could be considered no higher – and perhaps even lower – than in younger subjects. Because the risk of bleeding during anticoagulation treatment is higher in elderly subjects, three to six months of anticoagulant treatment in elderly patients with acute VTE is recommended. Extended anticoagulant treatment is not indicated in elderly patients, and any other decision should be carefully evaluated.⁵⁴

Start‐stop‐start anticoagulation

      Starting anticoagulation in elderly patients

      Sometimes, starting long‐term anticoagulation in an elderly patient is a complicated decision. In major functional impairment or when life expectancy is short, the benefit that anticoagulation could offer as primary prevention is questionable.

      On the other hand, acetylsalicylic acid has been classically considered an alternative to anticoagulation, especially in older patients (regardless of function), in hopes of minimizing the risk of bleeding. There is no current evidence to recommend using salicylic acetic acid in the primary prevention of patients with AF or as a prescription after initial anticoagulation in patients with VTE, and its use is associated with an increased risk of bleeding.^15,54

Older patients need closer monitoring during the first month of anticoagulation because the risk of bleeding is higher in this period.^55‐57 The elderly are at high risk of over‐anticoagulation at this time, particularly if standard rather than tailored induction doses are used. Siguret et al. have sought to develop a regimen for patients over 70,⁵⁸ giving 4 mg daily of warfarin for three successive days and the daily maintenance dose according to an algorithm; they found this protocol safe and accurate in elderly hospitalized patients.

      A crucial point to be considered is the patient’s preferences. It is important to explain the risks and benefits of anticoagulation. Providing adequate information and taking into account their opinion and preferences will result in better treatment adherence and thus fewer side effects.⁵⁹ In a recent study carried out in Spain, patients taking DOACs (versus VKAs) showed lower perceived burdens and higher perceived benefits with anticoagulation, regardless of many clinical variables including age, sex, level of dependency, renal function, number of pills, thromboembolic or bleeding risk, comorbidities, and duration of treatment with anticoagulants.⁶⁰

      Situations that force interruption of anticoagulation

      Intracranial bleeding (ICB)

      Based on observational studies, reinstitution of anticoagulation after ICB is associated with a lower risk of thromboembolic complications and a similar risk of intracranial haemorrhage recurrence. The recommendations regarding the best time to restart anticoagulation are not clear; we should consider the type of ICB (the risk of recurrence is greater in subarachnoid haemorrhage than intraparenchymal) and if the previous drug should be changed or replaced. More studies are needed for risk stratification for the subtype of stroke, localization and severity of ICB, and different anticoagulant drugs and exposure level.^61,62

      Surgical interventions

      In general, anticoagulant therapy should be stopped before the vast majority of surgical and other invasive procedures, but not stopping anticoagulant therapy is acceptable for low‐risk procedures with a risk of very minor or clinically insignificant bleeding.⁶³

      Based on the available evidence, the use of heparin bridging would only be for patients with a high thromboembolic risk. In patients being treated with a VKA, it is sufficient to start LMWH or UFH when the INR is less than 2 or, where this value is not available, when two to three doses of the drug have been omitted. Bridging therapy is not necessary with DOACs.

      It is recommended to resume anticoagulant therapy 24 hours after the procedure. As the anticoagulant effect of VKAs starts to set in at 24 to 72 hours, it is useful to manage heparin bridging therapy in patients with a high thromboembolic risk, but this recommendation is not necessary with DOACs. Reintroduction of oral anticoagulant therapy should be postponed for 48 to 72 hours only in patients with a high risk of postoperative bleeding.⁶³

      Poor control of the INR

      Maintaining an INR within the optimal range is more complicated as age increases, and labile INR is a risk factor for bleeding.⁶⁴ Reduced time in therapeutic range (TTR, percentage of time a patient’s INR is within the desired therapeutic range, using the linear interpolation method of Rosendaal) is related to higher mortality. When the INR is not suitably controlled (considering TTR <65% in the last six months), changing the anticoagulant treatment should be considered.

      Left atrial appendage closure could be a viable alternative to oral anticoagulation therapy for patients with NVAF who are considered poor candidates for long‐term oral anticoagulation or have any absolute contraindication. There is no current consensus on its indications and patient and device selection.⁶⁵

      Definitive interruption of anticoagulation

In general terms, the withdrawal of thromboprophylaxis should be considered when the risk of maintaining it exceeds the benefit it provides. The decision can be easy in the presence of major bleeding or an absolute contraindication but is much complicated out of this context. There are no validated tools that help

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