The increasing number of patients diagnosed with VTE/AF, combined with the complexities and patient co-morbidities that accompany these disorders, necessitates a multidisciplinary approach to patient management.

^*No dose adjustment is necessary in rivaroxaban- or apixaban-treated patients with mild (CrCl 50 - 80 ml/min) or moderate (CrCl 30 - 49 ml/min) renal impairment. Rivaroxaban and apixaban are to be used with caution in patients with severe renal impairment (CrCl 15 - 29 ml/min) and are not recommended in patients with CrCl < 15 ml/min. Dabigatran should only be used with caution in patients with moderate renal impairment (CrCl 30 - 50 ml/min). These patients should initiate their treatment within 1 - 4 hours following surgery with a single capsule of dabigatran 75 mg and continuing with two capsules (150 mg) od thereafter for a total of 10 days (knee replacement surgery) or 28 - 35 days (hip replacement surgery). Dabigatran is contraindicated in patients with CrCl < 30 ml/min. ^†Rivaroxaban-treated patients with moderate (CrCl 30 - 49 ml/min) or severe (CrCl 15 - 29 ml/min, rivaroxaban is to be used with caution in these patients) renal impairment should receive a reduced dose (15 mg od) if the patient’s assessed risk for bleeding outweighs the risk of recurrent DVT and PE (no dose adjustment is necessary in patients with mild renal impairment [CrCl 50 - 80 ml/min]). No dose adjustment is necessary in apixaban-treated patients with mild (CrCl 50 - 80 ml/min) or moderate (CrCl 30 - 49 ml/min) renal impairment, whereas in patients with severe renal impairment (CrCl 15 - 29 ml/min) apixaban should be used with caution. Dabigatran-treated patients with moderate renal impairment (CrCl 30 - 49 ml/min) should receive either a total daily dose of 300 mg or 220 mg based on bleeding risk, whereas no dose adjustment is necessary in patients with mild renal impairment. A reduced dose is also recommended or should be considered in other special patient populations. A reduced dose of edoxaban (30 mg od) is recommended in patients with one or more of the following: CrCl 15 - 50 ml/min, bodyweight ≤ 60 kg, patients receiving certain P-glycoprotein inhibitors. ^‡Rivaroxaban-treated patients with moderate (CrCl 30 - 49 ml/min) or severe (CrCl 15 - 29 ml/min) renal impairment should receive 15 mg od. The recommended dose of apixaban is 2.5 mg bid in patients with severe renal impairment (CrCl 15 - 29 ml/min) or with two or more of the following: age ≥ 80 years, bodyweight ≤ 60 kg or serum creatinine ≥ 1.5 mg/dl. Dabigatran-treated patients with moderate renal impairment (CrCl 30 - 49 ml/min) should receive a total daily dose of 300 mg or 220 mg based on the benefit-risk ratio. A reduced dose of edoxaban (30 mg od) is recommended in patients with one or more of the following: CrCl 15 - 50 ml/min, bodyweight ≤ 60 kg, patients receiving certain P-glycoprotein inhibitors. ^§No dose adjustment is necessary in rivaroxaban-treated patients with mild (CrCl 50 - 80 ml/min) or moderate (CrCl 30 - 49 ml/min) renal impairment. Approved for patients with elevated cardiac biomarkers also receiving a daily dose of 75 - 100 mg ASA or a daily dose of 75 - 100 mg ASA in addition to either a daily dose of 75 mg clopidogrel or a standard daily dose of ticlopidine. AF, atrial fibrillation; ASA, acetylsalicylic acid; bid, twice daily; CrCl, creatinine clearance; DVT, deep vein thrombosis; EU, European Union; od, once daily; PE, pulmonary embolism; VTE, venous thromboembolism.

The treatment of VTE and prevention of stroke in patients with AF is not restricted to the medical aspects (i.e. diagnosis and choice of medication), but also encompasses patient education, ongoing communication and organization of scheduled follow-up visits. Owing to constraints on their time, physicians focus predominately on the essential aspects of diagnosis and treatment, with less emphasis on non-medical aspects (e.g. patient education) [49] . Therefore, nurses are needed to not only complement the physician’s role but also coordinate all aspects of care and provide a more holistic approach to patient management.

Although a nurse-led multidisciplinary AF clinic can be implemented safely [50] , there has not been a prospective comparison between nurse-led care and usual physician care in patients with AF in the outpatient setting. In a randomized trial, integrated nurse-led chronic care was compared with routine clinical care in ambulatory patients with AF. The nurse-led care intervention consisted of guidelines-based software and cardiologist- supervised integrated chronic care. Nurse-led care was more efficacious compared with usual care with respect to the prevention of the composite of cardiovascular death and cardiovascular hospitalization. Patients on nurse-led care pathways were shown to be better informed about their disease status and possible ways of management. Guideline recommendations were also more comprehensively implemented in nurse-led care, possibly owing to the decision-support software, which was based on guidelines [50] . Notably, nurse-led care was also shown to be effective in challenging-to-treat patients with AF, including elderly patients with heart failure and previous stroke [50] .

^*Relating to issues other than bleeding. AF, atrial fibrillation; ASA, acetylsalicylic acid; DVT, deep vein thrombosis; GI, gastrointestinal; NSAID; non-steroidal anti-inflammatory drug; OAC, oral anticoagulant; PAI, platelet aggregation inhibitor; PE, pulmonary embolism; VKA, vitamin K antagonist, VTE, venous thromboembolism.

Guidance provided by the European Medicines Agency-approved Summary of Product Characteristics regarding the main contraindications of the non-VKA OACs for stroke prevention in patients with atrial fibrillation and for treatment and secondary prevention of venous thromboembolism [69] -[72] . ^*Dabigatran is contraindicated in patients with CrCl < 30 ml/min. Rivaroxaban and edoxaban are not recommended in patients with CrCl < 15 ml/min. ^†Dabigatran is contraindicated in patients with hepatic impairment or liver disease that is expected to have any impact on survival. See individual Summary of Product Characteristics for further details. CrCl, creatinine clearance; OAC, oral anticoagulant; VKA, vitamin K antagonist.

Patient education, improved adherence to guideline recommendations, time spent with patients, and teamwork between the nurse and the cardiologist were put forward as the essential elements behind the benefits of the nurse-led approach [50] . Within the context of a multidisciplinary team approach, the nurse specialist acts as the “centre” of a wheel of experts coordinating and driving the communication network between the patient, haematologist, cardiologist, pharmacist and general practitioner. A key responsibility assigned to the nurse in this scenario is direct communication with the supervising physician, outlining a detailed and accurate description of the patient’s current status. This can include the patient’s history, the indication for treatment, type of anticoagulant, dose and regimen, and co-medications. Nurses are also tasked with identifying the need for a switch to an alternative anticoagulant (i.e. decreased time within the therapeutic range, poor venous access, anticoagulation intolerability, patient request, compliance issues, laboratory test results, e.g. creatinine clearance [CrCl] levels). Nurses also carry out administrative duties (i.e. patient reminders for appointments, prescription refills, scheduling of routine laboratory testing, complete blood counts).

Patients with thromboembolic diseases commonly have additional medical conditions that may complicate their management. Challenging-to-treat patient groups often encountered in primary care include patients with renal impairment, diabetes, prior stroke/transient ischaemic attack or heart failure, and elderly patients. Anticoagulant therapy with VKAs can be challenging in such patients owing to numerous drug-drug interactions [29] . Nurses should be aware that the non-VKA OACs have fewer interactions with commonly used medications and that they have shown similar efficacy to warfarin with a consistent safety profile across a wide range of difficult-to- manage patient populations [51] - [55] . Nevertheless, nurses need to be aware of the most common patient groups that require closer follow-up and/or dose reductions with non-VKA OACs.

Patients likely to benefit from the non-VKA OACs include those poorly controlled on VKAs (i.e. those with a time in therapeutic range < 70%) [20] , patients requiring medications that interact with VKAs, those without severe renal impairment or those with a prior ischaemic stroke while on a VKA with an adequate INR. In keeping with a holistic approach to patient management, these agents may provide the physician with an alternative option to warfarin, and their use can be tailored to meet the individual needs of the patient. For instance, these agents would be a good choice for patients who have geographical/economic limitations (e.g. those who live a considerable distance from centres responsible for INR testing), lifestyle limitations that prohibit regular office or clinic visits (e.g. pilots, truck drivers, business people who travel), or even physiological limitations (e.g. poor venous access, prior stroke with dysphagia). However, some patients may prefer having their anticoagulation levels monitored regularly, including patients who are familiar and comfortable with VKA therapy or who have no prior history of bleeding/thromboembolic events while taking VKAs, and those in whom VKA therapy is well controlled. VKA therapy may be the preferred treatment in these cases. For patients on non-VKA OACs in whom adherence is poor despite regular education, switching to a VKA with a longer half-life could be a more suitable approach [56] . A practical consideration when deciding which anticoagulant to use in patients who are unable to swallow whole tablets (e.g. those suffering from dysphagia due to a prior stroke, patients with a gastrostomy tube or those with oesophageal stricture) would be whether the anticoagulant can be administered as a crushed tablet.

Convenience, costs, risk factors for bleeding and concerns about reversibility are some of the reasons why patients may wish to switch OAC agents. Switching between OACs is mainly based on the pharmacodynamic/ pharmacokinetic properties of these agents and recommendations derived from the results of the clinical trial programmes of each drug. Nurses should take a holistic view when considering whether a patient should be switched from a VKA to a non-VKA OAC or vice versa, ensuring that the patient is made aware of the reasons why a switch may be beneficial so that they can make an informed decision. Table 4 provides guidance for switching between anticoagulants.

The need for appropriate follow-up of patients receiving non-VKA OACs to ensure safe and effective anticoagulation treatment remains, despite the lack of a need for routine coagulation monitoring. For the treatment of VTE, a follow-up appointment or call would also help to ensure that the patient transitions smoothly from the acute to the longer-term phase of treatment, i.e. after the first 21 days of rivaroxaban or the first 7 days of apixaban treatment (Table 1), or from parenteral drug to oral dabigatran or edoxaban. Non-VKA OAC treatment of patients with thromboembolic diseases requires regular contact. Ideally, patients should have a follow-up visit every 3 months, and nurses can play a pivotal role in this regard [56] . Follow-ups provide opportunities for a nurse to carry out patient education as well as review critical aspects of patient management such as checking for adherence/compliance, signs of thromboembolic/bleeding events, side-effects (and other non-drug-related adverse events) and co-medications, and performing blood sampling for haemoglobin and renal function (CrCl), as well as assessing current weight and vital signs. In addition to the general “review list”, follow-ups provide the opportunity for the nurse and patient to develop a trusting relationship. When such a relationship develops, the patient is likely to benefit from the feeling that they have somebody to talk to who cares about their wellbeing. In turn, the patient is then more likely to be honest with the nurse about any issues with treatment, for example if they have missed a dose.

Nurses should always advise patients to bring their remaining medication to appointments, which will allow for an estimation of patient adherence. The assessment of compliance/adherence can be made by asking the patient specific questions about missed doses (or by inspecting the prescribed medication in blister packs), while making sure that the patient has not been switched to another anticoagulant by another healthcare provider. To further evaluate the understanding of the need for habitual taking of the medication as prescribed, the nurse could ask the patient, “If you missed a tablet, what did you do?” and “When did you take your next tablet?”. A more in-depth assessment of how a patient takes their medication can identify where compliance/adherence issues are arising. The nurse can then have a constructive discussion with the patient and provide suggestions as to how these issues could be prevented in the future (e.g. by changing the time of day the medication is taken, by making it part of the patient’s daily routine, by the patient carrying the medication with them if they are often out of the house). This provides the patient with the knowledge that they need in order to take responsibility and ownership of their disease state. For patients in whom poor adherence is suspected, technological aids may help, for example smartphone applications that remind the patient about the next drug intake. Nurses also need to ensure that the patient is aware of the over-the-counter medications associated with an increased risk of bleeding (i.e. non-steroidal anti-inflammatory drugs, acetylsalicylic acid) and highlight which medications are contraindicated and which should be used with caution. Thromboembolic and bleeding complications constitute crucial elements of the nurse’s checklist during follow-up and, if confirmed, these patients should be seen by a cardiologist and/or haematologist as soon as possible. In addition, caution should be taken to reduce the risk of falling, and the need for medications associated with an increased risk of falls (e.g. psychotropics, antidepressants and antipsychotics) should be reassessed [57] . Depending on the benefit-risk assessment, preventive measures

AF, atrial fibrillation; CrCl, creatinine clearance; DVT, deep vein thrombosis; INR, international normalized ratio; LMWH, low molecular weight heparin; OAC, oral anticoagulant; od, once daily; PE, pulmonary embolism; s.c., subcutaneous; UFH, unfractionated heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism.

(e.g. proton pump inhibitors) or drug-dose adjustments might be needed to reduce the risk of bleeding, especially when considering ongoing anticoagulation [56] .

Patients receiving a non-VKA OAC need to understand why regular kidney function monitoring is important. All of the non-VKA OACs are eliminated by the kidneys to some extent, unlike the VKAs, and periodic checks of CrCl levels are advised. It is of critical importance for patients to understand that they can continue their treatment safely providing their kidneys are functional and able to eliminate the drug. Patients receiving a non-VKA OAC and with CrCl ≥ 60 ml/min are recommended to have their renal function monitored on a yearly basis, whereas patients with CrCl 30 - 60 ml/min or CrCl ≤ 30 ml/min should be monitored every 6 and 3 months, respectively [56] . The use of serum creatinine or estimated glomerular filtration rate (eGFR) values alone may result in a misrepresentation of renal function. This is of particular relevance in elderly patients with low bodyweight [58] . It should be noted that the use of the eGFR is not interchangeable with the value obtained using the Cockcroft-Gault equation. Any patients with reduced renal function considered for non-VKA OAC treatment should have their CrCl accurately calculated using the equation―this was the method used in the pivotal phase III clinical trials and is recommended in the product labels. An example is outlined below for male and female gender:

For a man aged 65 years, weighing 85 kg with a serum creatinine of 74 µmol/l:

For a woman aged 70 years, weighing 50 kg with a serum creatinine of 80 µmol/l:

Exclusion of thrombocytopenia or anaemia (especially in elderly patients), assessment of other adverse events (i.e. dyspepsia and/or vomiting), advice on red flags (i.e. what happens if symptoms get worse and when to go to the Emergency Room [ER]) and optimal management of hypertension are aspects of patient management that need to be reviewed on a regular basis. Nurses should also keep track of difficult-to-manage patients (e.g. patients with substance dependency or intravenous drug users) because it is very likely that they will be in need of more frequent follow-up visits. Of note, close supervision by family members or caregivers will be required for patients with cognitive or memory deficits to ensure adherence/compliance.

Continuous patient education on their condition as well as treatment options and duration is of utmost importance (see Section 3.5). Various approaches could be employed in this regard, including face-to-face educational sessions and supplying leaflets/brochures with detailed instructions on how to initiate anticoagulation therapy and what is involved from the patient’s perspective. It is important that information is provided to patients at a level they can understand, in a manner that is timely and without overwhelming them. Nurses should avoid giving all the available information at once and should allow time for patients to digest and comprehend the most critical aspects of their disease and management. Patients also need to be given opportunities to ask questions such as, “Why has this happened to me?”, “When will the pain in my leg/lungs go away?”, “When will the clot go away?”, “Will my condition affect my everyday activities?” and “Why do I have to be on an anticoagulant and for how long?” Patients will often seek answers to practical issues concerning their everyday life such as whether they can drink alcohol, exercise or fly abroad. Much of the nurse’s role is also centred on educating patients to seek help when symptoms worsen or do not improve as expected. For example, ongoing shortness of breath, chest pain, coughing or vomiting blood for the newly diagnosed PE patient, or for the AF patient, ongoing shortness of breath or tachycardia that may indicate the need for further evaluation by a specialist. Further examination is also warranted in the case of ongoing pain, swelling or redness, or the appearance of new symptoms of shortness of breath or chest pain in patients with a current event of DVT. Nurses need to be confident in explaining to their patients how non-VKA OACs work, as well as the existing differences between them. All patients’ questions, fears and anxieties must be adequately addressed; unanswered or partially answered questions can cause misunderstandings with regard to treatment plan and duration. The most commonly reported fear associated with the use of anticoagulation is bleeding; therefore, as part of the ongoing education process, bleeding risk should be considered in context.

For example, the nurse might reassure a patient with AF who is taking an anticoagulant for stroke prevention by saying, “Yes, bleeding can be a frightening experience, but regardless of which anticoagulant you are taking, we (the doctors and nurses) will treat it using standard methods until it is under control. Bleeding is generally not caused by the anticoagulant and, therefore, it is important we investigate what else might have caused the bleeding.”

“Yes, it is true that VKAs have a reversal agent, but even that takes time to work. Non-VKA OACs do not remain in your body for very long, and ER physicians are able to manage your bleeding until the drug is eliminated from your body. If you are bleeding and need emergency care, it is important for the ER physician that you try to remember when your last dose was taken. This will help them to determine how much of the drug may still be circulating. There is a difference in the amount of circulating drug if you happened to take it an hour ago compared with 10 hours ago.”

The number of patients experiencing a serious bleeding event is low, whereas a stroke or PE can be fatal or permanently disabling. Real-world experience indicates that major bleeding rates in rivaroxaban- and dabigatran-treated patients are generally similar to or lower than those seen in VKA-treated patients [59] -[66] . Importantly, most major bleeding events in real-world patients treated with rivaroxaban can be controlled through conventional bleeding management protocols [59] . Minor bleeding (e.g. epistaxis, haemorrhoidal bleeding) does not mean that anticoagulation should be abruptly discontinued, because minor bleeding is usually temporary and not predictive of major bleeding (i.e. fatal/critical organ bleeding) [56] . The message that non-VKA OACs do not cause bleeding on their own should be reinforced, and nurses should assess for underlying causes that may have preceded the bleeding event (e.g. dry nasal mucous membranes, uncontrolled hypertension, peptic ulcer disease, diverticulitis). Patients should be made aware that because they are taking an anticoagulant, it will take longer for bleeding to stop. Bleeding risk in patients with AF can be reduced by managing the patient’s reversible risk factors for bleeding such as concomitant medications, non-steroidal anti-inflammatory drug use, co-morbidities such as hypertension and alcohol/drug misuse [67] . Data from the RIETE registry identified several risk factors (e.g. older age, cancer, immobility) that were independently associated with fatal bleeding in the first 3 months of VTE treatment (Table 5) [68] . Nurses should also encourage patients to use existing educational materials and to attend meetings of patient organizations (e.g. group education sessions) as a way of engaging patients in their care and improving outcomes.

AF, atrial fibrillation; CrCl, creatinine clearance; NSAID; non-steroidal anti-inflammatory drug; VTE, venous thromboembolism.