Outcomes in atrial fibrillation patients on combined warfarin & antiarrhythmic therapy

International Journal of Cardiology 167 (2013) 564–569

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Outcomes in atrial fibrillation patients on combined warfarin & antiarrhythmic therapy Annie Guérin a,⁎, Jay Lin b, Mehul Jhaveri c, Eric Q. Wu a, Andrew P. Yu a, Martin Cloutier a, Genevieve Gauthier a, Joseph S. Alpert d a

Analysis Group Inc., Boston, Massachusetts, USA Novosys Health, Flemington, New Jersey, USA sanofi-aventis Inc., Bridgewater, New Jersey, USA d Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona, USA b c

a r t i c l e

i n f o

Article history: Received 19 December 2011 Accepted 22 January 2012 Available online 14 February 2012 Keywords: Antiarrhythmic drug Warfarin Atrial fibrillation Amiodarone Cost

a b s t r a c t Background: This retrospective cohort study compared rates of treatment persistence, incidences of de novo stroke, arterial embolism, and hemorrhage/bleeding, and healthcare resource use and costs between atrial fibrillation/flutter (AF/AFL) patients receiving concomitant warfarin (W) + amiodarone (A) or warfarin + other antiarrhythmic drug (OAAD) therapy in real-world practice. Methods: The Ingenix IMPACT database (1997–2009) was used to identify patients with ≥1 diagnostic claim for AF/AFL and concurrent pharmacy claims (≥60 days' supply) for W and A (n = 4238) or W + OAAD (n = 6332) within the first 90 days of initiating therapy. Outcomes of interest were assessed over 12 months following initiation of dual therapy. Results: The W + A cohort was older than the W + OAAD cohort (mean 66.5 vs. 61.9 years) and had greater baseline comorbidity. The W + A cohort had significantly 1) lower rates of treatment persistence; 2) higher incidences of de novo stroke (hazard ratio [HR] 1.24), arterial embolism (HR 1.48) and combined stroke/hemorrhage/bleeding/arterial embolism (HR 1.25); 3) more frequent inpatient (incidence rate ratio [IRR] 1.25), emergency room (IRR 1.16) and outpatient (IRR 1.07) admissions; and 4) higher incidences of cardiovascular- (IRR 1.35) and arterial embolism- (IRR 1.94) related healthcare use than the W + OAAD cohort. Incremental total healthcare costs over 12 months were $4114 ($2397 inpatient; $1171 outpatient). Conclusions: Allowing for differences in prescribing practice, AF/AFL patients treated with W + A are at higher risk of stroke and arterial embolism, and have higher healthcare use and costs, than patients receiving W + OAAD. © 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Current recommendations for the management of atrial fibrillation (AF) and atrial flutter (AFL) include the use of antiarrhythmic drugs for restoration and/or maintenance of sinus rhythm [1,2]. Potential benefits of a rhythm-control strategy in AF/AFL include slowing of disease progression and improvement in symptoms, cardiac hemodynamics, exercise tolerance, and quality-of-life [3,4]. However, antiarrhythmic therapy does not obviate the need for long-term anticoagulation in AF/AFL, since patients with apparently successful restoration of sinus rhythm remain at embolic risk [5–7]. Amiodarone, the most widely used rhythm control agent in the United States

⁎ Corresponding author at: Analysis Group, Inc., 1000 rue de la Gauchetière Ouest, Bureau 1200, Montréal, QC, H3B 4W5, Canada. Tel.: + 1 514 394–4484; fax: + 1 514 394 4461. E-mail address: [email protected] (A. Guérin). 0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2012.01.047

(US) [8], is recommended as a second-line agent in the long-term treatment of AF in patients with structural heart disease and in highly symptomatic patients without heart disease [1,2]. Warfarin is the most commonly used oral anticoagulant in AF, and is recommended for patients at intermediate or high risk of embolic stroke [9]. Concurrent use of amiodarone and warfarin is, however, complicated by a drug-interaction that may potentially lead to excessive anticoagulation and hemorrhage [10–13]. Several observational cohort studies have compared clinical outcomes with long-term amiodarone + warfarin combination therapy vs. warfarin monotherapy in cardiac arrhythmia [11,12,14]. However, the warfarin + amiodarone combination has not been compared directly with warfarin + other antiarrhythmic drug combinations. This observational cohort study, using data from the Ingenix Impact National Managed Care Database (IMPACT) (1997–2009), compared treatment adherence, clinical outcomes, and healthcare resource use and costs among AF/AFL patients receiving warfarin with either amiodarone or other Class I/III antiarrhythmics.

A. Guérin et al. / International Journal of Cardiology 167 (2013) 564–569 2. Methods 2.1. Study design and patient selection The IMPACT database contains claims from approximately 60 million patients, from all census regions of the US, and covers 46 commercial health plans. Available information includes patient demographics, enrollment history, medical and pharmacy claims, and laboratory data. All data collected from the database were de-identified in compliance with the patient confidentiality requirements of the Health Insurance Portability and Accountability Act (HIPAA). For study inclusion, adult patients (≥18 years) were required to have at least one diagnostic claim for AF (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM]: 427.31) or AFL (ICD-9-CM: 427.32) within the 6-month period preceding initiation of dual warfarin/antiarrhythmic therapy, and pharmacy claims for at least 60 days' concomitant supply of warfarin and amiodarone or another Class I/ III antiarrhythmic drug within the first 90 days of commencing co-therapy. Patients were required to be continuously enrolled in a health plan for ≥6 months before and ≥12 months after the date of initiation of dual warfarin/antiarrhythmic therapy (‘index date’). Eligible patients were assigned to 1 of 2 mutually exclusive treatment cohorts: (1) the warfarin + amiodarone (W + A) cohort received these drugs concomitantly with no prior or on-study exposure to any other antiarrhythmic drug; and (2) the warfarin + other class I/III antiarrhythmic drug (W + OAAD) cohort received concomitant warfarin and either sotalol, propafenone, flecainide, dofetilide, quinidine, procainamide, disopyramide, or moricizine, with no prior or on-study exposure to amiodarone. The analyses included two study populations: (1) the full study population, which included patients with or without prior stroke, hemorrhage/bleeding, or arterial embolism (used for assessment of treatment persistence, healthcare resource use, and costs); and (2) a sub-population which specifically excluded patients with baseline stroke, hemorrhage/bleeding, or arterial embolism (used for assessment of de novo clinical outcomes). 2.2. Study outcomes Information on patient demographics (age, gender, geographic region) and baseline clinical characteristics (comorbidities, Charlson Comorbidity Index [CCI], cardiovascularrelated surgery/treatment, and use of medications with potential for interaction with warfarin) were collected for both treatment cohorts, using claims data for the 6-month pre-index period. Treatment persistence over the 12-month post-index follow-up period was defined as the time from treatment initiation to discontinuation of either index drug. Discontinuation was signified by a gap in prescription coverage of ≥60 consecutive days for either drug (the discontinuation date was the last day with drug supply before the 60-day gap). Patients were censored at first discontinuation of either index drug or on completion of the 12-month post-index follow-up period (whichever occurred first). Clinical events of interest, comprising stroke (ICD-9-CM: 430, 431, 432.0–432.9, 434.01, 434.11, 434.91), hemorrhage/bleeding (ICD-9-CM: 459.0x), and arterial embolism (ICD-9-CM: 444.xx), were identified from medical claims with a diagnosis (ICD-9CM code) of the relevant condition. Post-index follow-up was continued until either (1) first occurrence of the clinical event of interest; (2) 30 days after discontinuation of either index drug (for hemorrhage/bleeding only, since these events are unlikely to occur after treatment discontinuation); or (3) the end of patient eligibility or data availability (whichever occurred first). Event-related hospitalizations (inpatient stays with ≥ 1 diagnostic claim for the event of interest) and AF/AFL-related hospitalizations (inpatient stays with ≥ 1 cardioversion or intracardiac catheter ablation procedure) occurring during the 12-month post-index period were also identified, based on claims with a Current Procedural Technology (CPT), or ICD-9 procedure code for cardioversion (CPT: 92960, 92961), or intracardiac catheter ablation (CPT: 93650–93652, 93799, 33250–33251, 33254–33259, 33261, 33265–33266; ICD-9: 37.34). Healthcare resource utilization, including inpatient admissions, emergency room admissions, outpatient visits, and other medical services (laboratory, radiology, and other ancillary services), was estimated from claims data over the 12-month postindex period. In addition, total medical service resource utilization was separated into its constituent cardiovascular-, stroke-, AF/AFL-, hemorrhage/bleeding-, and arterial embolism-related components. Healthcare costs for medical services and pharmacy prescriptions were measured over the 12-month post-index period from a managed care perspective and were expressed in 2009 US$ values. Costs were separately categorized as all-cause and condition-related medical costs (i.e. costs of medical services associated with a diagnosis code for the specific condition). 2.3. Statistical analysis Baseline demographics and clinical characteristics were summarized with descriptive statistics, and inter-group differences were assessed using Wilcoxon rank-sum test (continuous variables) and chi-square test (categorical variables). Kaplan–Meier survival analysis was used to generate treatment persistence curves, and inter-cohort comparisons were performed using Log-ranks tests. Unadjusted and adjusted risks of clinical events were evaluated using Cox proportional hazards regression models, and results were reported as hazard ratios (HRs) and 95% confidence intervals (CIs).

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Adjusted incidence rate ratios (IRR) and 95% CIs for each type of healthcare resource use were estimated using Poisson regression models. Adjusted incremental medical and pharmacy costs were estimated using generalized linear models (GLM) with log link and gamma distribution or two-part models for cost components with more than 5% of patients with zero costs. Multivariate regression analysis was conducted to control for differences in demographics (age, gender, region of residence) and baseline clinical characteristics (comorbidities, cardiovascular surgery, number of days of warfarin and antiarrhythmic drug use during the baseline period, use of medication showing major interaction with warfarin, and baseline resource utilization and costs) between the study cohorts.

3. Results 3.1. Patient selection and baseline characteristics Of 307,443 patients identified in the database with a diagnosis of AF or AFL and at least one warfarin or amiodarone prescription, 10,570 patients met the study inclusion criteria (4238 in the W + A cohort; 6332 in the W + OAAD cohort) (‘Full Study Population’) (Fig. 1). A sub-group of 9947 patients with no prior history of stroke, hemorrhage/bleeding, or arterial embolism at baseline (3919 in the W + A cohort; 6028 in the W + OAAD cohort) was used for the clinical events analysis (‘Clinical Events Group’) (Fig. 1). Demographic and baseline (pre-index) clinical characteristics of the two treatment cohorts are detailed in Table 1. For the full study population, the W + A cohort was significantly older (mean 66.5 vs. 61.9 years), had higher baseline CCI and CHADS2 (Congestive heart failure, history of Hypertension, Age ≥75 years, Diabetes mellitus, and past history of Stroke or TIA) scores, and higher rates of cardiovascular comorbidity than the W + OAAD cohort, (Table 1). The W + A cohort had also experienced significantly shorter exposure to warfarin and antiarrhythmic drugs during the pre-index period (Table 1). Durations of follow-up (index date to end of eligibility) were similar for the W + A and W + OAAD cohorts (mean± SD: 138.1 ± 81.6 vs. 136.1 ± 77.6 weeks, respectively). The Clinical Events sub-population mirrored the full study population in demographic and baseline clinical characteristics and pre-index drug exposure (Table 1). For both study populations, the most commonly administered antiarrhythmics (W+ OAAD cohort) were sotalol (51% of patients), propafenone (20%), flecainide (19%), and dofetilide (6.0%). 3.2. Treatment persistence Among the full study population, persistence rates with dual therapy (i.e. both index drugs) were higher in the W + OAAD cohort than the W + A cohort at 3 months (86.0% vs. 80.9%), 6 months (63.4% vs. 51.5%), and 12 months (41.7% vs. 27.3%; p b 0.0001) postindex (Fig. 2). Similarly, the W + OAAD cohort showed significantly (p b 0.0001) higher persistence rates with W (56.6% vs. 48.3%) and antiarrhythmic drug therapy (67.1% vs. 46.9%) than the W + A cohort over the 12-month post-index period. After adjustment for inter-cohort differences in demographic and clinical variables, the W + A cohort was at significantly (p b 0.0001) higher risk of discontinuation of dual therapy [HR 1.54, 95% CI: 1.46–1.62], antiarrhythmic drug therapy (HR 1.92, 95% CI: 1.80–2.06) and warfarin therapy (HR 1.33, 95% CI: 1.25–1.42) than the W + OAAD cohort. 3.3. Clinical events Among the ‘Clinical Events Group’, the W + A cohort had significantly (p b 0.0001) higher incidences of stroke (6.6% vs. 4.2%, unadjusted HR 1.59), arterial embolism (2.4% vs. 1.1%, unadjusted HR 2.12) and combined stroke, hemorrhage/bleeding, and/or arterial embolism (9.3% vs. 5.7%, unadjusted HR 1.67) than the W + OAAD cohort, but the difference in hemorrhage/bleeding rates was not statistically significant (0.8% vs. 0.6%, unadjusted HR 1.54, p = 0.0761)

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Fig. 1. Patient identification and selection. AF: atrial fibrillation; AFL: atrial flutter; OAAD: other antiarrhythmic drug.

(Table 2). After adjustment for confounding factors, the W + A cohort was estimated to be at 24% higher risk of stroke (p = 0.0295), 48% higher risk of arterial embolism (p = 0.0272) and 25% higher risk of the combined end point of stroke, hemorrhage/bleeding and/or arterial embolism (p = 0.0083) than the W + OAAD cohort over the postindex period (Table 2). The risk of hemorrhage/bleeding (HR 0.91; p = 0.7330) did not differ significantly between the two cohorts (Table 2).

3.4. Healthcare resource use Among the full study population, the W + A cohort experienced significantly higher incidence rates of medical resource use, including inpatient and emergency room admissions, outpatient visits, and use of other medical services, than the W + OAAD cohort, and these differences remained significant after adjustment for confounding factors (Table 3). Before controlling for confounding

Table 1 Baseline (pre-index) demographic and clinical characteristics. Characteristic

Full study population

Clinical events group

W + A (n = 4238)

W + OAAD (n = 6332)

p-value

W + A (n = 3919 )

W + OAAD (n = 6028)

p-value

66.5 (9.5) 69.6

61.9 (10.1) 65.2

b 0.0001 b 0.0001

66.4 (9.6) 70.3

61.8 (10.1) 65.3

b 0.0001 b 0.0001

Mean baseline index drug use, days (SD) Warfarin 46.4 (68.6) Antiarrhythmic 21.7 (52.5) 2.30 (1.32) CHADS2 Index, mean (SD) CCI, mean (SD) 1.76 (1.63)

51.1 39.2 1.65 0.89

b 0.0001 b 0.0001 b 0.0001 b 0.0001

46.1 22.3 2.18 1.63

51.5 38.6 1.56 0.82

b 0.0001 b 0.0001 b 0.0001 b 0.0001

Comorbidities (%) Acute coronary syndrome Arterial embolism Congestive heart failure Deep vein thrombosis Heart failure Hemorrhage/bleeding Hypertension Ischemic heart disease Pulmonary embolism Stroke

0.9 0.9 29.5 1.0 18.0 0.2 61.8 34.5 1.8 3.8

b 0.0001 b 0.0001 b 0.0001 0.0806 b 0.0001 0.0100 b 0.0001 b 0.0001 0.0328 b 0.0001

2.0 0.0 58.1 1.2 46.4 0.0 67.0 55.8 2.1 0.0

Age, mean (SD) years Male (%)

2.2 2.0 59.1 1.3 47.2 0.5 67.9 56.5 2.5 5.4

(68.6) (67.6) (1.22) (1.20)

(68.4) (53.3) (1.24) (1.54)

0.8 0.0 29.0 0.8 17.6 0.0 61.3 34.2 1.7 0.0

(68.7) (67.2) (1.15) (1.13)

b 0.0001 b 0.0001 0.0706 b 0.0001 b 0.0001 b 0.0001 0.1346

W: warfarin; A: amiodarone; OAAD: other antiarrhythmic drug; SD: standard deviation; CHADS2: (congestive heart failure, history of hypertension, Age ≥75 years, diabetes mellitus, and past history of stroke or TIA) for atrial fibrillation; CCI: Charlson Comorbidity Index.

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4. Discussion

Fig. 2. Rates of persistence with combination therapy in the warfarin + amiodarone and warfarin + OAAD cohorts. OAAD: other antiarrhythmic drug.

factors, use of most medical service categories of interest, including cardiovascular-, stroke-, hemorrhage/bleeding-, and arterial embolism(but not AF/AFL-) related medical services, was more frequent in the W + A cohort than in the W + OAAD cohort (Table 3). After controlling for confounding factors, the W + A cohort displayed significantly higher incidences of cardiovascular- (adjusted IRR 1.35; p b 0.0001) and arterial embolism- (adjusted IRR 1.94; p = 0.0129) related medical service use, and a significantly lower incidence of AF/AFL-related medical service use (adjusted IRR 0.96; p = 0.0316) than the W + OAAD cohort (Table 3). Use of stroke- and hemorrhage/ bleeding-related medical services did not differ significantly between the two study cohorts (Table 3).

3.5. Healthcare costs Among the full study population, the total cost of healthcare (medical and pharmacy) claims in the unadjusted model was significantly higher (p b 0.0001) in the W + A cohort than in the W + OAAD cohort over the 12-month post-index period (mean $30,191 vs. $20,838 per patient) (Fig. 3). The major components of healthcare costs in both treatment cohorts were inpatient and outpatient costs. After adjustment for confounding factors, the average incremental total healthcare cost among the W + A cohort was $4114 per patient (p b 0.0001); this included significant incremental costs across all healthcare resource categories (inpatient $2397, outpatient $1171, emergency room $81, and other medical services $200) apart from pharmacy, for which costs were higher in the W + OAAD cohort ($384 per patient) (Fig. 3). The W + A cohort also incurred significant adjusted incremental cardiovascular-related medical costs of $1608 per patient (p b 0.0001); however, inter-cohort adjusted differences in AF/AFL-, stroke-, hemorrhage/bleeding-, and arterial embolism-related medical costs were minimal (b$100 per patient) and statistically non-significant (Fig. 3).

In this analysis we compared long-term clinical and economic outcomes between real-world cohorts of AF/AFL patients receiving warfarin and antiarrhythmic drug combination therapy. Among the patients identified for study inclusion from the IMPACT database, those in the W + A cohort were older and had higher rates of cardiovascular comorbidity than those in the W + OAAD cohort. Thus, in keeping with amiodarone's recommended role as a second-line treatment for AF/AFL [1], real-world patients selected for warfarin– amiodarone co-treatment would appear to have more complex and/ or advanced cardiovascular disease than those initiated on other warfarin–antiarrhythmic drug combinations. Overall, the results indicated that, after adjustment for these confounding factors, patients receiving combination warfarin and amiodarone therapy had significantly higher rates of treatment discontinuation (particularly of the antiarrhythmic drug), higher rates of de novo embolic events and higher healthcare resource utilization and costs than patients receiving warfarin and other antiarrhythmic drug combinations. After 12 months of follow-up, only 27.3% of patients initiated on warfarin + amiodarone remained on dual therapy compared with 41.7% of those on warfarin + other antiarrhythmic drug combinations. Over the 12-month post-index period, the W + A cohort experienced a 25% higher combined risk of stroke, hemorrhage/bleeding, and arterial embolism than the W + OAAD cohort. Assessment of individual clinical events showed, both before and after adjustment for confounding factors, significantly higher risks of arterial embolism and stroke in the W + A cohort. This increased risk of embolic events was associated with higher incidence rates of healthcare resource utilization — particularly medical resources related to management of arterial embolism — compared to the W + OAAD cohort. Additionally, over the 12-month postindex period, patients in the W + A cohort incurred significantly higher total healthcare (medical and pharmacy) costs, which were largely driven by higher inpatient medical costs. Difficulty in achieving anticoagulation control and concern about hemorrhagic risk are believed to contribute to early discontinuation of warfarin therapy [15], while lack of efficacy and concern about possible extra-cardiac toxicities are likely reasons for non-persistence with amiodarone therapy [16–18]. A recent community-based cohort study that tracked longitudinal warfarin use among ambulatory AF patients (n = 4188) reported that 26% of patients discontinued warfarin within the first year of treatment [15]. Since most (70%) of the patients in this cohort had ≥1 risk factor for AF-related stroke, and few had diagnosed risk factors for hemorrhage, the decision to discontinue warfarin is unlikely to have been based on safety concerns. In comparison, in the present study—which included patients from a broader segment of the US population—we found that almost half (47%) of all AF/AFL patients initiated on dual warfarin and antiarrhythmic drug therapy discontinued warfarin within the first 12 months. While many of these patients may have had clinically appropriate reasons for discontinuing warfarin (e.g. a low perceived risk of stroke), other factors, including concern about potential interactions between warfarin and non-antiarrhythmic drugs, may also be relevant. Persistence with amiodarone in this study was equally

Table 2 Unadjusted and adjusted hazard ratios (95% CI) for selected clinical adverse events in the warfarin + amiodarone cohort compared with the warfarin + OAAD cohort. Clinical event

W + A n = 3919 n (%)

W + OAAD n = 6028 n (%)

Unadjusted HR (95% CI)

p-value

Adjusted HR (95% CI)

p-value

Stroke, hemorrhage/bleeding, or arterial embolism Stroke Hemorrhage/bleeding Arterial embolism

364 (9.3%) 259 (6.6%) 31 (0.8%) 94 (2.4%)

341 (5.7%) 251 (4.2%) 38 (0.6%) 68 (1.1%)

1.67 1.59 1.54 2.12

b0.0001 b0.0001 0.0761 b0.0001

1.25 1.24 0.91 1.48

0.0083 0.0295 0.7330 0.0272

W: warfarin; A: amiodarone; OAAD: other antiarrhythmic drug; HR: hazard ratio; CI: confidence interval.

(1.44–1.94) (1.33–1.89) (0.96–2.48) (1.55–2.89)

(1.06–1.47) (1.02–1.49) (0.53–1.56) (1.05–2.10)

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Table 3 Comparison of all-cause medical resource utilization between the warfarin + amiodarone and warfarin + OAAD cohorts. Medical service

Unadjusted IRRa (95% CI)

p-value

Adjusted IRRa (95% CI)

p-value

Total medical services (all types) Inpatient admission Emergency room Urgent care Outpatient Other medical services

1.23 1.56 1.22 1.34 1.15 1.69

(1.20–1.26) (1.44–1.69) (1.09–1.36) (1.24–1.45) (1.12–1.18) (1.56–1.82)

b 0.0001 b 0.0001 0.0003 b 0.0001 b 0.0001 b 0.0001

1.11 1.25 1.16 1.19 1.07 1.34

(1.08–1.14) (1.15–1.35) (1.05–1.28) (1.11–1.28) (1.04–1.09) (1.24–1.44)

b 0.0001 b 0.0001 0.0042 b 0.0001 b 0.0001 b 0.0001

Total medical services Cardiovascular-related Stroke-related AF- or AFL-related Hemorrhage/bleeding-related Arterial embolism-related

1.92 1.85 0.89 2.24 3.11

(1.84–1.99) (1.25–2.72) (0.86–0.92) (1.26–4.00) (1.49–6.48)

b 0.0001 0.002 b 0.0001 0.0063 0.0025

1.35 1.23 0.96 1.26 1.94

(1.30–1.40) (0.89–1.71) (0.93–1.00) (0.74–2.15) (1.15–3.26)

b 0.0001 0.2141 0.0316 0.3911 0.0129

OAAD: other antiarrhythmic drug; IRR: incidence rate ratio; AF: atrial fibrillation; AFL: atrial flutter; CI: confidence interval. a IRR > 1 indicates that the warfarin + amiodarone cohort has a higher incidence of medical service use than the warfarin + OAAD cohort.

low, with 53% of patients discontinuing within the first 12 months, which closely matches the 56% discontinuance rate reported for amiodarone in an earlier retrospective database study of treatmentnaïve AF patients [19]. Several observational cohort studies have examined long-term (≤18 months) outcomes in patients receiving warfarin + amiodarone co-treatment [11,12]. However, in contrast to the present study, these earlier studies used warfarin alone as the reference treatment, involved small sample sizes, and were limited to measurement of surrogate end points (INR values, changes in warfarin dosage). Findings from these real-world studies indicate that maximum potentiation of the anticoagulant effect of warfarin occurs during the first two or three months of co-administration, with the drug interaction gradually diminishing on

continued treatment [11,12]. An administrative claims analysis that evaluated the relative hemorrhagic risk associated with various drug– drug and drug–disease interactions with warfarin reported that the likelihood of hemorrhage with the warfarin + amiodarone combination was no greater than that with warfarin alone [14]. However, this analysis provided no information on the duration of combination therapy, or on the extent of the drug interaction. The total costs of healthcare (medical and pharmacy) reported over the 12-month post-index period in this study (mean $30,191 vs. $20,838 per patient for the W + A and W + OAAD cohorts, respectively) approximate to earlier estimates of the direct treatment costs of AF [20,21]. A recent retrospective, observational cohort study using administrative claims from the MarketScan Commercial and Medicare

Fig. 3. Comparison of incremental healthcare costs associated with warfarin + amiodarone or warfarin + OAAD. ER: Emergency room; OAAD: other antiarrhythmic drug; AF/AFL: atrial fibrillation/flutter; CV: cardiovascular. a Total cost represents the sum of total medical and pharmacy costs. b Total medical cost represents the sum of inpatient, outpatient, ER and other medical service costs. c Adjusted for inter-cohort differences in demographics, comorbidity, pre-index antiarrhythmic and warfarin use, use of warfarin-interacting medication, cardiovascular surgery, and baseline resource utilization and costs. d Negative value indicates a lower cost for W + A compared with W + OAAD. *p b 0.05, **p b 0.01, ***p b 0.001.

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Supplemental research databases (2004–2006) estimated the total direct treatment cost of AF over the first 12 months after the index diagnosis at (mean) $20,670 per patient, and the net total incremental cost of AF at $8705 per patient (total direct cost $20,670 for AF patients vs. $11,965 for medically matched non-AF controls)[21]. Similarly, an earlier retrospective database study in the elderly US population reported the incremental direct treatment cost of AF over the 12month period following diagnosis to be (mean) $14,199 compared to Medicare beneficiaries without AF [20]. The present analysis is consistent with earlier studies [11,12] in suggesting that, over the long term, combination warfarin + amiodarone therapy does not increase hemorrhage/bleeding risk in AF/AFL patients. Nevertheless, use of this drug combination has clinical and economic implications for the real-world management of AF/AFL, since it is associated with an increased risk of arterial embolism and stroke, coupled with higher healthcare resource utilization and costs, compared with other warfarin + antiarrhythmic drug combinations. Administrative claims database do not provide detailed clinical information on the reasons underlying the provision of medical services. Accordingly, further investigation would be warranted to determine the cause of the observed increase in embolic risk with the warfarin + amiodarone combination. Premature discontinuation of warfarin, resulting in inadequate anticoagulation, is a possible explanation, although other factors may also be relevant. The study cohorts differed in several baseline characteristics, notably the presence of heart failure (more common in the W+A cohort), which predisposes toward hemorrhage with warfarin [22]. While we controlled for the potential demographic and clinical confounders available in the claims database, residual confounding due to imbalance in nonidentified covariates cannot be excluded. This study was of limited follow-up duration, and longer follow-up may be required to determine the absolute incidence of rare clinical events, such as stroke. Furthermore, given the constraints of the administrative claims data, specific information on the contribution of treatment discontinuation or drug– drug interaction to the observed clinical outcomes was not available. This again is an area for possible future investigation. 5. Conclusion In real-world clinical practice, AF/AFL patients initiated on warfarin + amiodarone combination therapy appear to be less persistent with treatment, to be at greater embolic risk, and to incur higher healthcare resource use and costs than those receiving warfarin + other antiarrhythmic drug combinations. Acknowledgements Financial and editorial support for the development of this manuscript was provided by sanofi-aventis, Inc. Dr. Alpert is a research consultant to Bayer, Boehringer-Ingelheim, Johnston & Johnston, sanofi-aventis Inc., and Servier, and has served on advisory boards for sanofi-aventis Inc. and Boehringer-Ingelheim. Dr. Jhaveri is an employee of sanofi-aventis, Inc. Dr. Lin is an employee of Novosys Health, which has a research consulting agreement with sanofi-aventis, Inc. Drs. Guerin, Wu, Yu, Cloutier, and Gauthier are employees of Analysis Group, which has a research consulting agreement with sanofiaventis, Inc.

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