Table 2.

Unmet clinical need and potential answer for any subset considered in the text

Subset	Unmet clinical need	Potential answer
Comorbidity and frailty in the elderly	There is no single definition of frailty, and there are no universal scales to assess it	Comorbid and frail patients could benefit from DOACs, and the decline in cardioembolic complications has a more substantial impact than the small increase of bleeding complications related to their use. DOACs have a better risk–benefit profile than VKAs in this population
Elderly patients with chronic kidney disease	Calculated CrCl and eGFR are discordant in elderly patients with very low renal function making a relevant clinical impact when choosing the appropriate dose of DOAC	Anti-Xa inhibitors are the preferable DOACs for elderly patients when the eGFR is 15–30 mL/min/1.73 m2. No substantial evidence supports treatment with DOACs when the eGFR rate is < 15 mL/min/1.73 m2, although their use may be reasonable in selected patients
Elderly patients with non-valvular AF and ischemic stroke	The early introduction of DOACs after acute ischemic stroke remains challenging as patients were excluded from RCTs if they had an ischemic stroke 7–30 days before enrolment	The benefit of early anticoagulation should be balanced with the risk of ICH, especially in elderly patients and in severe strokes. Early introduction of DOACs might be reasonable in elderly patients because their risk of recurrent ischemic stroke is higher than that of ICH
Cardioversion of non-valvular AF in the elderly	There is a paucity of data on cardioversion of NVAF in the elderly. VKAs require ongoing dosing management to maintain a therapeutic effect, and cardioversion may be delayed when INR levels are sub-therapeutic	When cardioversion is necessary to improve symptoms, the treatment approach for older patients is the same as for younger patients. DOACs have a more rapid onset and consistent anticoagulation level, allowing a more rapid and precise cardioversion strategy than VKAs also in the elderly
Antithrombotic therapy after PCI in the elderly	Data regarding the optimal antithrombotic combination therapy in patients undergoing stenting and suffering from NVAF can be challenging to apply in the real world. The competing ischemic and bleeding risks are even more difficult to disentangle in elderly patients, at best, underrepresented in RCTs	Choices must be personalized and involve an in-depth discussion between clinical and interventional cardiologists, including other specialists (geriatricians, endoscopists, rehabilitation specialists) in many cases
Elderly patients with non-valvular AF and cancer	In patients with NVAF and cancer, no clinical scores for predicting thromboembolic events were validated. However, they are currently used along with an evaluation of the type of cancer and concomitant therapies. The risk of stroke is likely to be underestimated in NVAF and cancer, while the bleeding risk depends on cancer and comorbidities	DOACs seem to offer higher protection from stroke or systemic embolism than warfarin in patients with NVAF and cancer. A multidisciplinary approach is necessary to evaluate thromboembolic and bleeding risks, drug–drug interactions, and patient preferences
Management of DOACs in elderly patients undergoing an invasive procedure or surgery	Conversely to VKAs discontinuation, thrombotic risk assessment is far less relevant than the bleeding risk assessment that should be used as the main determinant of DOAC discontinuation strategy for invasive procedure or surgery	In patients at risk for relevant residual drug concentrations and elderly with renal impairment, it might be helpful to run routine lab testing before high-risk surgery or invasive procedures. When stopping DOACs, it is suggested to use a prophylactic dose of heparins for VTE only, as in patients with NVAF undergoing the same type of surgery. Restarting full-dose DOAC at least 48–72 h after surgery is probably safer
Pharmacokinetic characteristics of DOAC and drug interactions	Most of the recommendations for using DOACs in polytreated patients are based on in vitro experimental data, and only a few pharmacokinetic studies have been performed to verify the extent of the variation of DOAC plasma concentrations	The use of DOACs with lower inter-patient and intra-patient variability of plasma concentrations and less susceptible to CYP3A4 enzymatic activity would be safer

AF atrial fibrillation, CrCl creatinine clearance, DOAC direct oral anticoagulant, eGFR estimated glomerular filtration rate, ICH intracranial haemorrhage, INR international normalized ratio, NVAF non-valvular atrial fibrillation, PCI percutaneous coronary intervention, RCT randomized clinical trial, VKA vitamin K antagonist, VTE venous thromboembolism