ABC | Volume 114, Nº3, March 2020

Original Article Silva et al. Warfarin therapy in NVAF patients in Brazil Arq Bras Cardiol. 2020; 114(3):457-466 per member per year (PMPY), in Brazilian Reals (R$) and converted to US dollars. A conversion factor of 0.33 USD/BRL was obtained by averaging the daily exchange rates within each year of the study period (May 1, 2014 to April 30, 2016). The daily exchange rates were obtained from historical records of a public currency exchange calculator. 17 Out-of-pocket costs were not included. Finally, key characteristics, clinical and economic outcomes were observed and compared amongst TTR quartiles. Statistical methods Due to the exploratory nature of the study, key characteristics and outcomes were descriptively analyzed. Descriptive statistics were reported as counts, percentages, means, medians, standard deviations and quartiles. Continuous variables were described as mean and standard deviation or median and respective interquartile range, depending onwhether or not a normal distributionwas found. Categorical variables were described as frequencies and percentages. Comparisons were made between continuous variables using an independent unpaired two-sample t -test and between categorical variables using the chi-square test. P-values < 0.05 in two-tailed tests were considered statistically significant. All analyses were carried out using SAS 9.4. Subgroup analysis The key characteristics, clinical and economic outcomes were analyzed for the overall population and for patients with poor (TTR < 65%) and good (TTR ≥ 65%) control. Sensitivity analysis To check for main analysis consistency, some patient characteristics, INR, TTR levels and PMPY costs were observed for a group of patients followed for at least 6 months with records of the calls in at least 50% of the months during the study period. Results Patient characteristics A total of 1,220 patients with NVAF were included for the main analysis (Figure 1). Overall, median follow-up was 1.5 years (interquartile range [IQR]: 0.5–2.0 years). Key patient characteristics are listed in Table 1. The mean age was 63.9 ± 14.7 years and 50.7% were females. The mean CHA 2 DS 2 -VASc score was 2.45 ± 0.88. Most patients (85.7%) were from the Southeast region of Brazil. Approximately 10% of patients were on concomitant statin therapy and a minority of patients (~4%) were receiving concomitant antiplatelet therapy with aspirin and/or Clopidogrel. Hypertension was the most prevalent comorbidity (38.5%), followed by heart failure (19.8%), prior stroke (13.7%) and diabetes (13.6%). Anticoagulation control Each patient had a mean of 15.63 (±9.13) INR tests over a median of 18 months of follow-up, equivalent to approximately 0.95 tests per month. The mean INR value was 2.60 ± 0.88, the median INR value was 2.44 (IQR: 1.99 – 3.00). Among all measured INR values, 49.1% were within the therapeutic range (2.0–3.0), whereas 26.1%of all INR values were<2.0, and 24.8% were>3.0 (Figure 2A). Themedian andmean patient‑level TTRs were 58% (IQR 47%–68%) and 56.6% (±18.9%), respectively. The TTR distribution is reported in Figure 2B. Only 377 patients (31%) exhibited good control (TTR ≥ 65%) and 843 patients (69%) had poor control (TTR < 65%). Clinical outcomes Among all patients, the major and minor bleeding rates of patients in the program were 4.2% and 10.3%, respectively (Figure 3). The major bleeding rate among well-controlled patients (TTR ≥ 65) was 1.6%, whereas it was 5.3% for poorly controlled patients (TTR<65%). Therefore, the major bleeding rate was 3.3 times higher in poorly-controlled patients when compared with well-controlled patients (p < 0.01). While the trend was not as strong with minor bleedings, fewer minor bleeds were observed in subgroups with highest TTR. An exploratory analysis was conducted to observe the closest INR value prior to the event on a sample of patients admitted for a stroke. Out of 15 patients, 12 (80%) experienced a hemorrhagic or unspecified stroke event, despite having an INR within the therapeutic range 2-3 (Supplementary information). Economic outcomes The PMPY cost across the entire cohort was R$32,284 (USD$10,679). Inpatient costs represented ~64% of all costs (R$20,710 or USD$6,851); outpatient costs represented ~36% (R$11,573 or USD$3,828). The mean INR monitoring cost PMPY was R$362 (USD$120), ranging from R$296 (USD$98) to R$417 (USD$138) and representing < 1% of the total direct costs (Table 2). The PMPY cost was R$25,352 (± R$37,762) or USD$8,386 (±USD$12,492) per well-controlled patient (TTR ≥ 65%) and R$35,384 (± R$50,900) or USD$11,705 (± USD$16,838) per poorly-controlled patient (TTR < 65%). Thus, patients with suboptimal warfarin control were associated with 40% higher costs, on average (p < 0.01). PMPY costs with and without major bleeds were R$62,145 (USD$20,558) and R$30,981 (USD$10,249), respectively. In all cases, inpatient costs were greater than outpatient costs (Table 2). Metrics per TTR quartile Some key characteristics and outcomes were observed across TTR quartiles to see which, if any, were more prevalent in patients with lower TTR compared with the overall population and patients with higher TTR. As shown in Table 1, patients with lower TTR were more often females, had more comorbidities (diabetes, renal disease, heart failure), fewer INR tests and a lower overall monitoring period. Sensitivity analyses A total of 934 patients were included in the sensitivity analyses. An identical mean INR value of 2.60 ± 0.96 and a similar median INR (2.43; IQR: 2.00-3.00) were observed 459