Non-persistence to Oral Anticoagulation Treatment in Patients with Non-valvular Atrial Fibrillation in the USA

In this study, we pooled five large national claims databases with the latest available data at the time of application. They included 100% fee-for-service US Centers for Medicare and Medicaid Services data (1 January 2012–31 December 2017), Truven MarketScan^® Commercial Claims and Encounter (1 January 2012–30 June 2019), IMS PharMetrics Plus™ (1 January 2012–31 March 2019), Optum Clinformatics™ Data Mart (1 January 2012–31 March 2019), and the Humana Research Database (1 January 2012–31 March 2019). Of note, patients with Medicare supplemental plans in Truven MarketScan and IMS PharMetrics Plus data were not included in the study to avoid potential duplicates with Medicare Part A and Part B. More details on the datasets and pooling method have been published [15, 16].

We identified adult patients with NVAF between 1 January 2012 and 30 June 2019 using inpatient and outpatient claims, and selected patients with a pharmacy claim for apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin during the identification period between 1 January 2013 and 30 June 2019. Each patient’s first OAC was labeled as their “index therapy,” and the date of the first OAC prescription claim was labeled as the “index date.” Patients prescribed edoxaban were not included in the final analysis because of the small sample size (N = 1629). Patients were required to have continuous medical and pharmacy health plan enrollment for ≥ 12 months before the index date [17].

We excluded patients with any OAC treatment within 12 months before the index date to ensure they were treatment naïve. We also excluded patients with evidence of valvular heart disease, venous thromboembolism, transient AF (pericarditis, hyperthyroidism, or thyrotoxicity), or heart valve replacement or transplant during the baseline period; pregnancy during the study period; or hip/knee replacement surgery within 6 weeks before the index date. To give all patients the possibility of discontinuing/switching index treatment, we also excluded patients with more than one OAC on the index date and those with fewer than 60 days of follow-up, based on continuous health plan enrollment post-index.

Patient data were assessed from the day after the index date until the earliest of the following: end of continuous medical and pharmacy enrollment, death (when available), or end of the study period. The primary outcome of interest was non-persistence, defined as either discontinuation or switch, with discontinuation defined as no evidence of the index OAC prescription for ≥ 60 days from the last day of supply of the last filled prescription and switch defined as filling a prescription for an OAC other than the index drug during the follow-up period within ± 60 days of last days’ supply from the index OAC.

Baseline variables included demographics (age, sex, US geographic region) and clinical characteristics such as clinical risk scores, prior stroke/systemic embolism (SE), prior bleeding, comorbidities, and baseline medication use.

Descriptive analysis of clinical and demographic variables was conducted for patients prescribed DOACs or warfarin. Rates of non-persistence among patients with NVAF who initiated an OAC during the identification period were calculated during the follow-up period overall and at 12 months post-index date. Unadjusted Kaplan–Meier survival curves were generated to illustrate time to non-persistence in addition to cumulative incidence of non-persistence. Cox proportional hazard models with robust sandwich estimates were used to compare the risk of non-persistence across treatment groups while adjusting for patient covariates. Baseline variables included in the model were patient demographics, index OAC prescription, and clinical characteristics such as prior stroke/SE, prior bleeding, comorbidities, and baseline medication use.

A secondary analysis was conducted taking into consideration clinical events occurring after the index date, including stroke/SE hospitalizations, major bleeding (MB) hospitalizations, new acute renal failure (considered new when it occurred for the first time within a timeframe of 6 months), new chronic renal failure (considered new when it occurred for the first time after the index date), new cancer diagnoses (considered new when it occurred for the first time within a timeframe of 6 months), and cardioversions and catheter ablations [18]. The diagnosis codes used for stroke/SE and MB hospitalizations were based on validated administrative claims-based algorithms and the International Society on Thrombosis and Haemostasis definition of MB [19, 20].

We conducted three sensitivity analyses:

In total, 1,021,112 adults with NVAF were newly prescribed an OAC during the study period (Fig. 1). Of those patients, 363,823 (35.6%) initiated apixaban with a mean ± standard deviation follow-up of 605 ± 410.5 days; 57,121 (5.6%) initiated dabigatran with a mean follow-up of 939.3 ± 566.4 days; 282,831 (27.7%) patients initiated rivaroxaban with a mean follow-up of 799.7 ± 524.4 days; and 317,337 (31.1%) patients initiated warfarin with a mean follow-up of 892 ± 543.7 days. Approximately 53% of patients in all treatment groups combined were male. The mean age of patients receiving apixaban, dabigatran, rivaroxaban, and warfarin was 75.1 ± 10.6, 73.4 ± 10.3, 73.5 ± 10.7, and 76.7 ± 9.3 years, respectively. Patients initiating warfarin were older and were at higher risk in terms of the CHA₂DS₂-VASc score (4.5 ± 1.8) and HAS-BLED score (3.2 ± 1.4) (see Table 1 for CHA₂DS₂-VASc and HAS-BLED definitions) and had higher mean Deyo–Charlson Comorbidity Index scores of 3.4 ± 3.0. For those receiving apixaban, dabigatran, or rivaroxaban, 22.6% (2.5 mg), 15.6% (15.2% on 75 mg; 0.4% on 110 mg), and 25.8% (5.4% on 10 mg; 20.4% on 15 mg) had lower dosage regimens, respectively (Table 1).

The cumulative incidence of non-persistence at 3 months was 21.2, 33.9, 28.8, and 26.7% for patients receiving apixaban, dabigatran, rivaroxaban, or warfarin, respectively (Fig. 2). The cumulative incidence of non-persistence at 12 months was 42.7, 58.9, 52.2, and 51.3% for patients receiving apixaban, dabigatran, rivaroxaban, or warfarin, respectively (Fig. 2). Most of the non-persistence was because of discontinuation of therapy, but 3–9% of patients switched treatment, with dabigatran having the highest switch rate (Table 2).

Figure 3 and Table 3 show the results of primary analyses with Cox models that adjusted for demographic and clinical covariates defined at baseline. When compared with those receiving warfarin, patients initiating apixaban (adjusted hazard ratio [aHR] 0.74; 95% confidence interval [CI] 0.74–0.75; P < 0.001) or rivaroxaban (aHR 0.98; 95% CI 0.97–0.98; P < 0.001) were 26 and 2% less likely to be non-persistent, respectively. Patients receiving dabigatran (aHR 1.21; 95% CI 1.19–1.22; P < 0.001) were 21% more likely to be non-persistent than those receiving warfarin.

When compared with patients receiving rivaroxaban, those initiating apixaban (aHR 0.76; 95% CI 0.75–0.76; P < 0.001) were 24% less likely to be non-persistent. Those receiving dabigatran (aHR 1.23; 95% CI 1.22–1.25; P < 0.001) were 23% more likely to be non-persistent than those receiving rivaroxaban. When compared with patients receiving dabigatran, those initiating apixaban (aHR 0.62; 95% CI 0.61–0.62; P < 0.001) were 38% less likely to be non-persistent.

Older age and history of hypertension and stroke/SE were predictors of a lower likelihood of non-persistence (Table 3). Patient use of statins was also a predictor of reduced risk of non-persistence.

Table 1 in the electronic supplementary material (ESM) shows the proportion of patients with time-varying clinical events after the index date, and Table 4 shows the model results when time-varying covariates were included in Cox models. The HRs for OACs remained consistent after the inclusion of time-varying covariates. All time-varying clinical characteristics were significant predictors of non-persistence: stroke/SE aHR 1.57; 95% CI 1.53–1.61; MB aHR 2.96; 95% CI 2.92–3.00; new acute renal failure aHR 1.44; 95% CI 1.42–1.46; new chronic renal failure aHR 1.14; 95% CI 1.12–1.15, new cancer aHR 1.22; 95% CI 1.20–1.25; and cardioversions and catheter ablations aHR 1.17; 95% CI 1.15–1.19. All HRs were significant at P < 0.001.

The effect of a change to the definition of the discontinuation gap from 60 to 30 days is shown in Tables 2, 4 and Fig. 1 in the ESM. As expected, there was an increase in non-persistence for all OACs, but the results for the comparative risk of non-persistence across DOACs did not change significantly.

As with many real-world studies, our study has several limitations. This study was designed to examine non-persistence among patients with NVAF initiated on OACs and predictors of non-persistence, so we could not evaluate causal relationships. As is the nature with retrospective observational studies, our study was subject to confounders. This study was bound by the limitations of the claims data; variables such as over-the-counter use of aspirin, serum creatinine/creatinine clearance, and laboratory values were unavailable and thus were not controlled for in the model. Codes from the International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification were used to identify baseline characteristics and outcomes, which may lack clinical accuracy. Additionally, we were unable to determine time in therapeutic range for patients prescribed warfarin or jointly assess the relationship between persistence and adherence. Furthermore, we were unable to identify predictors related to cost or access. Our results might in fact have been driven by non-medical reasons, including out-of-pocket costs, formulary changes, insurance changes, physician preferences, and access issues, which we were unable to capture but have been documented as possible indicators for treatment switch or discontinuation [29].

Nevertheless, our study is a major contribution to the literature on real-world persistence with OAC, since it is by far the largest retrospective observational study, with over 1 million patients, examining the comparative risk of non-persistence between OACs. By pooling five datasets and including a comprehensive comparison of the OACs, this study adds supplemental information to the literature and may assist in decisions around treatment selection for stroke prevention among patients with NVAF. The robustness of our findings is evidenced by the similar results observed after limiting follow-up to the initial 12 months after OAC initiation, shortening of the gap length from 60 to 30 days, and the inclusion of INR results in lengthening warfarin treatment line.