Compliance and adherence to oral anticoagulation therapy in elderly patients with atrial fibrillation in the era of direct oral anticoagulants.

Thromboembolic complications represent a substantial problem in patients with atrial fibrillation (AF). The prevalence of AF burden and associated arterial and venous thrombosis progressively increases with age. At the same time, representative national data regarding stroke incidence in AF patients aged 80 and older are limited.[1] The largest observational Framingham Study demonstrated that up to 23.5% of strokes in octogenarians were attributable to AF.[2] A higher risk of ischemic events is present in elderly; and is associated, among other factors, with underuse of continuous anticoagulation.[3] Data from several clinical trials demonstrated an increased rate of major bleeding in patients treated with vitamin K antagonists (VKA), and was reported to increase by 46% for every 10 years after the age of 40 despite therapeutic anticoagulation.[1],[4]–[6] Potential predisposing factors for bleeding events in this age group include low body mass index, altered body composition of muscle and fatty tissue, and a higher prevalence of renal impairment.[1],[7],[8]

Direct oral anticoagulants (DOACs, which include dabigatran, rivaroxaban, apixaban, and edoxaban) have been shown effective in stroke prevention in general AF population,[9],[10] while data regarding DOACs safety profile in elderly patients are scarce.[11]–[13]

Recent data demonstrate DOACs advantages over warfarin, especially for older population: more predictable dosing, fewer drug interactions and reduced risk of intracranial bleeding.[14]

A large meta-analysis of efficacy and safety parameters of DOACs in elderly adults provided data from 10 randomized clinical trials with 25,031 participants.[15] Risk of bleeding was reported not different between Warfarin and DOACs group therapy in older population [odds ratio (OR) = 1.02, 95% confidence interval (CI): 0.73–1.43], while DOACs were associated with equal or greater efficacy. Similar results were observed in four AF trials where DOACs were more effective than vitamin-K antagonists in prevention of stroke or systemic embolism in participants aged 75 and older.[16]–[19]

Preventive medical therapy is effective when it is persistent. Generally, therapy discontinuation is driven by a clinical reason (for instance, bleeding), or is explained by patient non-compliance or non-adherence.

The average rate of VKA therapy discontinuation has been reported 30% during first year, and up to 50% within 3 years following treatment initiation.[8],[20] In addition, up to 40%–50% of AF patients do not even start with VKA therapy, mostly due to a fear of complications.[21]

The World Health Organization provides the following explanation to the adherence: “the extent to which a person's behaviour—taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health care provider”, with strong emphasis placed on the need to differentiate adherence from compliance. The main difference is that “adherence requires the patient's agreement to the recommendations”.

Most frequently, adherence to therapy is limited by the complexity of the regimen (the number of medicines and the frequency of administration) and failure of a patient and/or his relatives to understand the importance of compliance. However, there are a number of other reasons why people do not adhere or comply with their medication regimen: social/economic-related factors (economic status, medication cost); survivor-related factors (forgetfulness, treatment anxiety, misunderstood instructions, fear of becoming dependent on medication); medication-related factors (length of treatment, unwanted side effects); condition-related factors (level of disability, severity of the condition). With age, the relevance of these limitations grows substantially.

DOACs are less likely to be discontinued, because there is no need for ongoing monitoring, they have stable dosage regimen, and a lesser interaction with other drugs. This has to be associated with improved anticoagulation therapy compliance and adherence.[22] Surprisingly, studies showed that DOACs' non-adherence reached 50% if no special measures are being taken.[23]–[25]

A retrospective cohort study evaluated discontinuation rates of DOACs in comparison with Warfarin in 24,596 AF patients.[26] After age and gender adjustments, patients taking apixaban were less likely to discontinue the drug (P < 0.0001 for all comparisons versus other anticoagulants).

In a large US registry with about 6000 participants multiple daily dosing of anticoagulants was negatively associated with medication compliance in patients with venous thromboembolism, whereas once daily dose regimen contributed to approximately 39%–61% higher likelihood of adherence.[27] Further results from the Dresden non-interventional oral anticoagulation registry demonstrated that 223 of 2600 patients (18.5%) stopped rivaroxaban during a mean follow-up period of 544 days, which translates into a discontinuation rate of 13.6 (95% CI: 11.8–15.4) per 100 patient-years (15% in the first year and very low thereafter). Overall persistence with rivaroxaban therapy was much higher than reported for VKA in all age groups, while most common reasons for DOACs discontinuation were bleeding complications (30% of all discontinuations), followed by other side-effects (24.2%) and diagnosis of stable sinus rhythm (9.9%).[22] These results of higher treatment persistence with DOACs are in line with the findings of other studies. Data from large German observational trial provide analysis of real-world persistence and adherence to oral anticoagulation for stroke risk reduction in patients with atrial fibrillation.[28] During follow-up, estimated treatment persistence was found to be significantly greater for patients receiving rivaroxaban than for patients receiving VKA, both at 180 days (66.0 vs. 58.1%; P < 0.001) and at 360 days (53.1 vs. 25.5%; P < 0.001) after treatment initiation. Interestingly, dabigatran also demonstrated higher persistence compared with VKA (60.3% vs. 58.1% at 180 days), but the difference was not statistically significant. At day 360, the difference between the dabigatran and warfarin groups came up to statistically significant level (P < 0.001) while rivaroxaban demonstrated a better persistence compared with dabigatran (P = 0.026). Among factors that may contribute to improved adherence in DOAC groups are fixed dosing and fewer food or drug interactions along with lack of regular international normalized ratio (INR) monitoring. Differences in adherence and persistence between rivaroxaban and dabigatran may possibly be related to their side-effect profiles and dosing regimens. Patients, especially while taking lifelong medications, generally prefer once-daily rivaroxaban dosage. It also should be noted that some clinical trials and DOAC registries indicated a clinically relevant dyspepsia rate for dabigatran (> 11% of all patients in RE-LY), which was not seen with VKA or rivaroxaban.[22],[29],[30]

Another recent retrospective cohort study testing oral anticoagulation treatment adherence in AF patients included 3986 participants (32.9%) with initiated DOACs and 8143 individuals on warfarin.[31] Overall, 47.3% of patients independently discontinued treatment during follow-up (416.6 ± 141.7 days) with mean time to discontinuation of 120 ± 114.7 days. Patients on DOACs had a significantly lower discontinuation rate, when compared to warfarin group or patients with several comorbid conditions. Patients with prior bleeding were more likely to discontinue. Among elderly AF patients the risk of independent treatment discontinuation remained high (HR: 0.32; 95% CI: 0.24–0.43). In contrary, four recent randomized trials on DOACs in 21 062 AF patients > 75 years old provided substantial evidence for their efficacy and demonstrated better compliance compared to VKA in this age group, that could potentially be associated with stable dosage regimen and lack of laboratory monitoring.[15]

Two recently published articles in Journal of Geriatric Cardiology analyzed anticoagulation in old AF patients. In a study by Kwon,et al.[32] the authors evaluated 293 Asian octogenarian AF patients > 75 years old receiving oral anticoagulation with either warfarin or DOACs. The efficacy end point was the composite of stroke or systemic embolism, whereas the safety outcome was major bleeding. Reported incidence of stroke or systemic embolism was low in old patients, with no significant difference between DOACs and warfarin groups (1.16% vs. 2.98% per 100 patient-years, correspondingly, P = 0.46). At the same time, bleeding complications tended to be less frequently encountered in the DOACs group; however, this trend was not statistically significant (8.96% vs. 12.46%, P = 0.29).

Another study by Annoni, et al.[33]provided characteristics of 1619 hospitalized patients > 80 years old with and without AF. The objective of this study was to explore the clinical characteristics of elderly AF subjects, and factors that may decrease the persistence of stroke prophylaxis therapy. The authors found that the majority of old patients with AF were frail and had a combination of comorbidities. Importantly, the authors discussed potential anticoagulation therapy in elderly subjects, in whom previously (in the era of VKA) chronic anticoagulation was considered unsuitable because of adherence or safety issues. The authors noted that under-prescription of anticoagulation therapy should not be explained by the old age only.

We would like to emphasize that therapy adherence plays an important role in chronic prophylactic therapy. Inconsistent anticoagulation therapy in AF patients may be associated with a worse outcome and a higher risk of stroke-associated disability. VKA drugs are known to have a fluctuating profile of action, but patient adherence/compliance can be verified by regular INR tests. INR control, sometimes uncomfortable and even annoying for patients, provides some degree of assurance in physician's prescription implementation. With introduction of DOACs, drugs generally associated with better adherence, evaluation of therapy persistence has not become easier. Available screening coagulation tests, such as the activated partial thromboplastin time and prothrombin time, may be useful for DOACs' effect evaluation in special clinical situations (urgent treatment discontinuation, bleeding, and thrombosis). However, the sensitivity of these tests does not meet the clinicians' demands. A higher risk of non-compliance and non-adherence to oral anticoagulants in everyday practice, in comparison with those evaluated in sponsored clinical trials, may potentially lead to underestimation of bleeding risk and/or suboptimal stroke prevention in observational and cross-sectional studies.

Some measures have been proposed to improve drug therapy adherence: continuous education of patients and their relatives, education brochures and posters, use of pill organizers, medication trackers.

We urge that in prospective studies, assessing safety and efficacy of DOACs in old patients, special attention should be paid to medication adherence.

In conclusion, elderly patients with AF usually have more concomitant conditions that affect compliance and adherence to anticoagulant therapy. DOACs seem to be associated with better adherence; however, there is still room to improve continuous coagulation control and adherence among elderly AF patients receiving anticoagulants in everyday practice.