CLINICAL RESEARCH STUDY

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1 CLINICAL RESEARCH STUDY Warfarin Use and Outcomes in Patients with Atrial Fibrillation Complicating Acute Coronary Syndromes Renato D. Lopes, MD, PhD, a Aijing Starr, a Carl F. Pieper, DPH, b Sana M. Al-Khatib, MD, MHS, a L. Kristin Newby, MD, MHS, a Rajendra H. Mehta, MD, MS, a Frans Van de Werf, MD, PhD, c Kenneth W. Mahaffey, MD, a Paul W. Armstrong, MD, d Robert A. Harrington, MD, a Harvey D. White, DSc, e Lars Wallentin, MD, f Christopher B. Granger, MD a a Duke Clinical Research Institute, Duke University Medical Center, Durham, NC; b Department of Biostatistics and Bioinformatics, School of Medicine, Duke University, Durham, NC; c Department of Cardiology, University Hospital Gasthuisberg and Leuven Coordinating Center, Leuven, Belgium; d Department of Medicine, Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada; e Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand; f Uppsala Clinical Research Center, Uppsala, Sweden. ABSTRACT BACKGROUND: We examined warfarin use at discharge (according to Congestive heart failure, Hypertension, Age 75 years, Diabetes, Prior Stroke/transient ischemic attack score and bleeding risk) and its association with 6-month death or myocardial infarction in patients with post-acute coronary syndrome atrial fibrillation. METHODS: Of the 23,208 patients enrolled in the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy, Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network A, and Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors trials, 4.0% (917 patients) had atrial fibrillation as an in-hospital complication and were discharged alive. Cox proportional hazards models were performed to assess 6-month outcomes after discharge. RESULTS: Overall, 13.5% of patients with an acute coronary syndrome complicated by atrial fibrillation received warfarin at discharge. Warfarin use among patients with atrial fibrillation had no relation with estimated stroke risk; similar rates were observed across Congestive heart failure, Hypertension, Age 75 years, Diabetes, Prior Stroke/transient ischemic attack (CHADS 2 ) scores (0, 13%; 1, 14%; 2, 13%) and across different bleeding risk categories (low risk, 11.9%; intermediate risk, 13.3%; high risk, 11.1%). Among patients with in-hospital atrial fibrillation, warfarin use at discharge was independently associated with a lower risk of death or myocardial infarction within 6 months of discharge (hazard ratio 0.39; 95% confidence interval, ). CONCLUSION: Warfarin is associated with better 6-month outcomes among patients with atrial fibrillation complicating an acute coronary syndrome, but its use is not related to CHADS 2 score or bleeding risk Elsevier Inc. All rights reserved. The American Journal of Medicine (2010) 123, KEYWORDS: Acute coronary syndrome; Antithrombotics; Atrial fibrillation; Bleeding risk Funding: The Duke Clinical Research Institute. Conflict of Interest: The authors state that they have no conflict of interest regarding the content of the article. Authorship: All authors had access to the data and played a role in writing this manuscript. Reprint requests should be addressed to Renato D. Lopes, MD, PhD, Duke University Medical Center Box 3850, Durham, NC address: renato.lopes@duke.edu. Atrial fibrillation not only is the most common cardiac arrhythmia seen in clinical practice but also commonly complicates myocardial infarction. 1-3 In a pooled analysis involving more than 120,000 patients with both ST-segment elevation myocardial infarction and non ST-segment elevation acute coronary syndrome, we found the overall incidence of post-acute coronary syndrome atrial fibrillation was 7.5%. 4 Moreover, atrial fibrillation in the setting of myocardial infarction is clinically relevant given its inde /$ -see front matter 2010 Elsevier Inc. All rights reserved. doi: /j.amjmed

2 Lopes et al Warfarin Use and Outcomes in Post-Acute Coronary Syndrome Atrial Fibrillation 135 pendent association with worse short- and long-term outcomes. 4-7 Although diagnosing atrial fibrillation is usually straightforward, the optimal treatment strategy, particularly after an acute coronary syndrome, is poorly defined because its occurrence is usually transient and there are challenges associated with several antithrombotic agents already being used for the treatment of the acute coronary syndrome event. Although the use of vitamin K antagonists in patients with atrial fibrillation reduces the risk of stroke by approximately 62%, 8 little is known about the use of and need for oral anticoagulant therapy in patients with atrial fibrillation complicating an acute coronary syndrome. The objective of this study is to examine warfarin (and other antithrombotic agents) use at discharge (according to Congestive heart failure, Hypertension, Age 75 years, Diabetes, Prior Stroke/transient ischemic attack score and bleeding risk score) 9,10 and its association with 6-month death or myocardial infarction in patients with post-acute coronary syndrome atrial fibrillation. CLINICAL SIGNIFICANCE Only 13.5% of patients with an acute coronary syndrome complicated by atrial fibrillation received warfarin at discharge. Warfarin is associated with better 6- month outcomes among patients with atrial fibrillation complicating an acute coronary syndrome, but its use is not related to Congestive heart failure, Hypertension, Age 75 years, Diabetes, Prior Stroke/transient ischemic attack (CHADS 2 ) score or bleeding risk. Among the components of the CHADS 2 score, the only significant predictor of warfarin use at discharge was heart failure. METHODS We conducted these analyses using a pooled database of 23,208 patients with non ST-segment elevation acute coronary syndrome who were enrolled in clinical trials and in whom information on atrial fibrillation as an in-hospital complication and use of oral anticoagulation at discharge was available. This population comprised patients from the following trials: Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), 11 Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network A (PARAGON-A), 12 and Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/ IIIa Inhibitors (SYNERGY). 13 Details of these trials were published previously. Briefly, these trials were randomized and conducted in multiple countries throughout the world. Patients were enrolled from 1995 to 1996 (PARAGON-A), 1995 to 1997 (PURSUIT), and 2001 to 2003 (SYNERGY). Inclusion criteria included chest pain, changes on electrocardiogram (ST-segment deviations), and positive biomarkers of myocardial necrosis. Atrial fibrillation was defined as an irregularly irregular rhythm with lack of discernible P waves on an electrocardiogram any time during the hospital course after randomization. It was identified as a complication on the patient s case report form. Information about type, duration, or history of atrial fibrillation was not available. The primary clinical outcome of this study was adjudicated death or myocardial infarction at 6 months. Myocardial infarction was defined by elevated biomarkers (2 upper limit of normal) or electrocardiographic evidence (new and significant Q waves in 2 contiguous leads). Statistical Methods Baseline characteristics are presented as medians with 25th and 75th percentiles for continuous variables and frequencies and percentages for categorical variables. Comparisons between patients based on warfarin use were made using the Wilcoxon rank-sum test for continuous variables and the chi-square or Fisher exact test (when the expected frequency count in a cell is 5) for categorical variables. The relation between warfarin use and Congestive heart failure, Hypertension, Age 75 years, Diabetes, Prior Stroke/transient ischemic attack score was assessed at discharge. Therefore, the Congestive heart failure, Hypertension, Age 75 years, Diabetes, Prior Stroke/transient ischemic attack score and the bleeding score were calculated at discharge. Congestive heart failure, Hypertension, Age 75 years, Diabetes, Prior Stroke/transient ischemic attack (CHADS 2 ) score at discharge was calculated by assigning 1 point each to history of hypertension, age 75 years or more, history of congestive heart failure or left ventricular ejection fraction 35% or less, and history of diabetes mellitus. Two points were given for history of stroke or transient ischemic attack. Bleeding risk factors included age 65 years or more, history of stroke, history of gastrointestinal bleed, recent hematocrit less than 30%, serum creatinine concentration greater than 1.5 mg/dl, or history of diabetes mellitus. Patients without any risk factors were categorized as low risk, patients with 1 to 2 risk factors were categorized as intermediate risk, and patients with 3 to 4 factors were categorized as high risk. 10 Multivariable Cox proportional hazards models were constructed to identify the association between 6-month death or myocardial infarction and use of antithrombotic drugs at discharge. In addition to antithrombotic drugs (aspirin, ticlopidine/ clopidogrel, and warfarin), variables considered for the model were in-hospital coronary artery bypass graft surgery, gender, heart rate, smoking status, and CHADS 2

3 136 The American Journal of Medicine, Vol 123, No 2, February 2010 score; these were selected on the basis of prior studies of risk factors for mortality in the population with non STsegment elevation acute coronary syndrome. 14 As a sensitivity analysis, a multivariable analysis using propensity score risk adjustment also was performed. The proportional hazard assumption was assessed in smoothing spline-based score tests. Only variables with a significant (P.05) association with death/myocardial infarction by stepwise selection were included in the final model. Adjusted hazard ratios and accompanying 95% confidence intervals were computed to determine the association of warfarin use with death/myocardial infarction. The 6-month mortality curves were constructed with stratification by warfarin use using the Kaplan Meier method. SAS version 8.0 (SAS Institute, Cary, NC) software was used for all analyses. This analysis was supported by the Duke Clinical Research Institute. RESULTS Of the 23,208 patients enrolled in the PURSUIT, PARAGON-A, and SYNERGY trials, 5.8% (1346 patients) had atrial fibrillation as an in-hospital complication and 4.0% (917 patients) had atrial fibrillation and were discharged alive. Data on long-term outcomes were complete in 97% of the patients. Baseline Characteristics According to Warfarin Therapy Patients who received warfarin at discharge more often had a history of heart failure, diabetes, myocardial infarction, and stroke and less often had a history of hypertension when compared with patients who did not receive warfarin at discharge (Table 1). Otherwise, the baseline characteristics were similar between the 2 groups. Medications at Discharge and In-hospital Procedures According to Warfarin Therapy The discharge medications and in-hospital procedures according to warfarin use are shown in Table 2. Compared with patients who did not receive warfarin at discharge, patients who did receive warfarin at discharge were more likely to be discharged with an antiarrhythmic drug, a calcium channel blocker, an angiotensin-converting enzyme inhibitor, and a nitrate, and less likely to receive aspirin and a beta-blocker. Warfarin Use According to Congestive Heart Failure, Hypertension, Age > 75 Years, Diabetes, Prior Stroke/Transient Ischemic Attack Score and Bleeding Risk Warfarin use among patients with atrial fibrillation was similar across CHADS 2 scores: 0, 13%; 1, 14%; 2, 13% (Figure 1). Among patients with atrial fibrillation, aspirin and ticlopidine/clopidogrel use rates also were similar across CHADS 2 scores. Of the components of the CHADS 2 score, only prior heart failure had a statistically significant association with warfarin use at discharge (odds ratio 1.5; 95% confidence interval (CI), ; P.04). The use of warfarin according to bleeding risk is shown in Figure 2. Warfarin was used similarly and approximately 12% of the time, regardless of the risk of bleeding. Notably, as the risk of bleeding increased, the CHADS 2 score followed the same pattern that illustrates the overlap of clinical factors associated with the risk of both stroke and bleeding. Patients at high risk of bleeding had a median CHADS 2 score of 4, and 11.1% received warfarin; the rate of warfarin use was similar (11.9%) for patients at low risk of bleeding, and the median CHADS 2 score was 1. Despite the increase in the median CHADS 2 score, the use of aspirin and ticlopidine/clopidogrel decreased as the risk of bleeding increased (Figure 2). Although patients who had prior stroke were more likely to receive warfarin at discharge (20%) than patients without a previous stroke (13%), the use of warfarin was low in both groups (Figure 3). Patients with a prior stroke were less likely to receive aspirin or ticlopidine/clopidogrel at discharge. Six-Month Death or Myocardial Infarction Factors associated with 6-month death or myocardial infarction are shown in Table 3. Warfarin use at discharge was strongly associated with a lower risk of death or myocardial infarction within 6 months (adjusted hazard ratio 0.39; 95% CI, ; P.04) (Figure 4). In the sensitivity analysis, after adjusting for the propensity of receiving warfarin at discharge, similar results were found; warfarin use at discharge was significantly associated with lower rates of the 6-month outcome of death or myocardial infarction (hazard ratio 0.38; 95% CI, ; P.04). Other In-hospital Complications According to Warfarin Use at Discharge Compared with patients who did not receive warfarin at discharge, patients who did had less in-hospital severe bleeding (0.8% vs 2.5%), less ventricular fibrillation (24.2% vs 36.6%), less sustained ventricular tachycardia (25.8% vs 35.9%), more in-hospital stroke (3.2% vs 1.4%), more congestive heart failure (21% vs 15.6%), more sustained hypotension (15% vs 12%), more cardiogenic shock (6.5% vs 2.5%), and more transient ischemic attack (2.5% vs 0.5%). DISCUSSION Our study has 3 main findings. First, we demonstrated that warfarin use is associated with a lower risk of 6-month death or myocardial infarction in patients with atrial fibrillation complicating an acute coronary syndrome. Second, although atrial fibrillation guidelines recommend warfarin use based on CHADS 2 score, 15 we showed that the use of warfarin was independent of both the estimated stroke and bleeding risks; this also was true of other antithrom-

4 Lopes et al Warfarin Use and Outcomes in Post-Acute Coronary Syndrome Atrial Fibrillation 137 Table 1 Baseline Characteristics According to Warfarin Use at Discharge Parameter All Patients (n 917) Warfarin (n 124) No Warfarin (n 793) P Value Age, median (25th, 75th), y 69.0 (62.0, 74.4) 68.0 (62.0, 73.7) 69.0 (62.0, 75.0).33 a Female Race.57 White Black Other Smoking status.80 Never Previous Current Killip class.50 b I II III IV Region.43 b North America Western Europe Eastern Europe Latin America Australia Other Weight, median (25th, 75th), kg 79.0 (69.0, 90.0) 78.5 (66.4, 87.5) 79.0 (69.0, 90.0).32 Height, median (25th, 75th), cm (164.5, 177.8) (162.6, 177.8) (165.0, 177.8).27 BP, median (25th, 75th), mm Hg Systolic (116.0, 145.0) (115.0, 140.0) (116.0, 146.0).49 a Diastolic 72.0 (64.0, 80.0) 70.5 (63.0, 80.0) 72.0 (64.0, 80.0).51 a Heart rate, median (25th, 75th), 75.0 (64.0, 85.0) 76.0 (62.0, 88.0) 75.0 (65.0, 85.0).84 a beats/min Prior CABG Prior hypertension Prior CHF Prior diabetes mellitus Prior PCI Prior MI Proportion of US patients Prior CVA, stroke, or TIA BP blood pressure; CABG coronary artery bypass graft surgery; CHF congestive heart failure; CVA cardiovascular accident; MI myocardial infarction; PCI percutaneous coronary intervention; TIA transient ischemic attack. Data presented as percentages unless otherwise indicated. a Nonparametric test. b Exact test. botic medications. Finally, we identified several factors that are strongly associated with a risk of 6-month death or myocardial infarction, including CHADS 2 score 2. Antithrombotic therapy is indicated for the treatment of both acute coronary syndromes and atrial fibrillation. 15,16 However, for patients with an acute coronary syndrome and atrial fibrillation, the use of combinations of different antithrombotic agents may significantly increase the risk of bleeding. Rothberg et al 17 showed that the combination of aspirin and warfarin for patients with myocardial infarction is associated with lower mortality compared with the use of aspirin alone; however, bleeding rates are higher. Unfortunately, these questions could not be addressed in our study because of the lack of data on long-term bleeding. We showed that patients at high risk for bleeding are at high risk for stroke as well, and warfarin was prescribed similarly to patients at low risk for stroke. This illustrates the overlap between the clinical factors associated with both stroke and bleeding and that physicians are making the decision to use warfarin on the basis of other (unmeasured) factors. The use of antiplatelet agents, however, was lower in patients at higher risk of bleeding despite their increased risk of stroke. Thus, bleeding risk is related to the decision not to prescribe antiplatelet agents for patients with atrial fibrillation after acute myocardial infarction, even when the stroke risk is high.

5 138 The American Journal of Medicine, Vol 123, No 2, February 2010 Table 2 Discharge Medications and In-hospital Procedures According to Warfarin Use at Discharge Parameter Warfarin (n 124) Discharge medications Aspirin Digitalis Ticlopidine/clopidogrel Beta-blockers Calcium channel blockers Nitrates ACE inhibitors Antiarrhythmics In-hospital catheterization In-hospital PCI In-hospital CABG No Warfarin (n 793) ACE angiotensin-converting enzyme; CABG coronary artery bypass graft surgery; PCI percutaneous coronary intervention. Data are presented as percentages. Figure 2 Antithrombotic use according to bleeding risk. CHADS 2 Congestive heart failure, Hypertension, Age 75 years, Diabetes, Prior Stroke/transient ischemic attack. In an observational study, Stenestrand et al 18 showed that patients with atrial fibrillation and myocardial infarction who receive warfarin and a platelet inhibitor had lower 1-year mortality compared with those who received aspirin alone. Approximately 7.5% of their patients had atrial fibrillation and were discharged alive. The population of this study included patients with ST-segment elevation and patients with ST-segment depression acute coronary syndrome, and 30% of the patients with atrial fibrillation and acute myocardial infarction received oral anticoagulant therapy at discharge. Although our study was limited to patients with non ST-segment elevation acute coronary syndrome and the use of warfarin was lower than in previous studies, our analysis included patients enrolled in large randomized clinical trials in which variables were prospectively defined and data were prospectively collected. We demonstrated that although international guidelines 16,19 recommend warfarin for patients with atrial fibrillation and clear indication for anticoagulation, this recommendation tended not to be followed in those with postacute coronary syndrome. In patients with in-hospital atrial fibrillation and prior stroke (CHADS 2 score of at least 2), in whom warfarin use is generally indicated, warfarin was only prescribed approximately 20% of the time at hospital discharge (Figure 2). Concordant with the findings of the present study, we previously showed an inverse relationship between the CHADS 2 score and warfarin use in patients with post STsegment elevation myocardial infarction atrial fibrillation. 20 This might relate to the observation that patients with a higher CHADS 2 score are at an increased risk of both stroke and bleeding. Thus, the set of patients who might benefit most from warfarin tended not to receive it, perhaps because of concerns over subsequent risk of bleeding. This scenario Figure 1 Antithrombotic use according to CHADS 2 score. CHADS 2 Congestive heart failure, Hypertension, Age 75 years, Diabetes, Prior Stroke/transient ischemic attack. Figure 3 stroke. Medication given at discharge based on prior

6 Lopes et al Warfarin Use and Outcomes in Post-Acute Coronary Syndrome Atrial Fibrillation 139 results in an apparent paradox patients with a higher CHADS 2 score have lower warfarin use. Moreover, patients at high risk for ischemic stroke who also are at high risk for bleeding received warfarin in similar proportion to those at low risk for stroke. However, this explanation is largely speculative and needs to be verified in future studies. We showed previously that patients with ST-segment elevation myocardial infarction and atrial fibrillation who received warfarin at discharge had lower rates of both 90- day mortality and stroke when compared with those patients who did not receive warfarin at hospital discharge. 20 In the present study, we demonstrated that both warfarin and aspirin use at discharge were independently associated with lower rates of 6-month death or myocardial infarction. Therefore, although only 14% of the patients received warfarin at discharge, our study supports the guidelines in their recommendation to consider the use of warfarin and aspirin in patients with non ST-segment elevation acute coronary syndrome and atrial fibrillation. The timing of atrial fibrillation in the setting of an acute coronary syndrome also is an important issue that should be taken into consideration. In the present study, we described patients with non ST-segment elevation acute coronary syndrome who developed in-hospital atrial fibrillation as a complication. We do not have information about the patients rhythm at discharge. Siu et al 21 demonstrated that transient atrial fibrillation in the setting of acute myocardial infarction is an independent predictor of future development of atrial fibrillation and stroke. We showed previously that the majority of patients who developed atrial fibrillation in the setting of an acute myocardial infarction were not in atrial fibrillation at the time of hospital discharge. 20 Therefore, even if most of our patients with atrial fibrillation were not in atrial fibrillation at the time of discharge, our results raise the possibility that even if the atrial fibrillation is transient, patients have better outcomes if they receive warfarin at discharge. Table 3 Predictors of 6-month Death or Myocardial Infarction in Patients with Atrial Fibrillation and Acute Coronary Syndrome Variable HR (95% CI) Chi-square P Value In-hospital CABG 0.30 ( ) CHADS 2 score ( ) Warfarin at discharge 0.39 ( ) Aspirin at discharge 0.47 ( ) CABG coronary artery bypass graft surgery; CHADS 2 Congestive heart failure, Hypertension, Age 75 years, Diabetes, Prior Stroke/ transient ischemic attack; CI confidence interval; HR hazard ratio. Figure 4 Adjusted 6-month death or myocardial infarction curves according to warfarin use at discharge. MI myocardial infarction. Study Limitations Our study has some limitations. First, because of the observational study design, we cannot conclude cause and effect relationships between atrial fibrillation, its treatment, and outcomes. It is possible that most or even all of the association of warfarin use and better outcome relates to unmeasured confounders. Second, we did not collect data on postdischarge bleeding or stroke. We also do not have information about international normalized ratio control in the patients who received warfarin, which might influence our findings. Third, we had a relatively small number of events; however, we accounted for that when building our statistical models to avoid overfitting. Finally, we were unable to determine the timing, duration, and type of atrial fibrillation (paroxysmal, persistent, or permanent) and whether or not patients had a history of atrial fibrillation predating the acute coronary syndrome; therefore, we could not examine the effect of these variables on our findings. CONCLUSIONS Warfarin is associated with better 6-month outcomes among patients with atrial fibrillation complicating an acute coronary syndrome, but its use is infrequent and not related to stroke or bleeding risks. Among the components of the CHADS 2 score, the only significant predictor of warfarin use at discharge was heart failure. CHADS 2 score 2 was independently associated with worse outcomes. Antiplatelet agents, particularly ticlopidine/clopidogrel, were less often prescribed in patients at higher risk of bleeding. 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