Heart Fail Rev DOI 10.1007/s10741-014-9420-4
Atrial fibrillation in heart failure: stroke risk stratification and anticoagulation JoEllyn M. Abraham • Stuart J. Connolly
Ó Springer Science+Business Media New York 2014
Abstract For an individual patient with both atrial fibrillation and heart failure, stroke risk is one of the most prominent mitigating factors for subsequent morbidity and mortality. Although the CHADS2 stroke risk score is the most widely used score for risk stratification, it does not take into account the risk factors of vascular disease, female gender, or the age group 65–74 years, for which there is increasing evidence. There is also evidence that diastolic heart failure is as much a risk factor for stroke as systolic heart failure. The new oral anticoagulants dabigatran, rivaroxaban and apixaban appear to be appropriate agents in the heart failure population with atrial fibrillation and risk factors for stroke although there are dose-adjustments for renal insufficiency and these medications are contraindicated in advanced renal disease. As with the atrial fibrillation population as a whole, bleeding risk should be considered for every patient with heart failure prior to making recommendations regarding anticoagulation. Keywords Heart failure Atrial fibrillation Stroke Anticoagulation
Epidemiology of heart failure and atrial fibrillation Heart failure and atrial fibrillation are diagnoses that frequently co-exist in the same population. Indeed, of those
J. M. Abraham (&) Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, J2-2, Cleveland, OH 44195, USA e-mail: [email protected] S. J. Connolly Division of Cardiology, McMaster University, Hamilton, Canada
with a diagnosis of atrial fibrillation, about 40 % will develop a concomitant diagnosis of heart failure and the reverse is true as well [1, 2]. Most recent estimates suggest that there are 2.7 million individuals with atrial fibrillation in the USA, with a prevalence of 0.5 % in individuals younger than 60 years old and 8.8 % in octogenarians and those older (overall prevalence approximately 1 %). Further, atrial fibrillation is more common in men than women (1.1 vs. 0.8 % overall prevalence and 3 vs. 1.7 % in patients aged 65–69) [3, 4]. The prevalence of heart failure in the USA is even higher, with the disease affecting roughly 5.1 million individuals (approximately 2 % of the population) [2, 4]. The prevalence of atrial fibrillation increases with increasing New York Heart Association (NYHA) Class, and it appears to be similar for heart failure with both preserved and reduced systolic function [5, 6]. For both conditions, the prevalence is projected to continue to increase in the foreseeable future [4]. For an individual patient with both atrial fibrillation and heart failure, stoke prevention is an important medical concern. About 15 % of strokes in the USA are thought to be caused by atrial fibrillation [3]. It is important to emphasize that while thromboembolism is the most common cause for stroke in the population with atrial fibrillation, up to 25 % of strokes in this population occur secondary to other etiologies such as aortic and carotid atherosclerotic disease and microvascular disease from underlying hypertension [7, 8]. This statistic underscores the importance of risk factor modification for this population when making assessments of embolic stroke risk. This review article will aim to cover some of the unique challenges of assessing risk of stroke as well as those of deriving safe and effective stroke prevention strategies in patients with both of these comorbidities.
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Stroke risk in patients with heart failure and sinus rhythm It has long been recognized that patients with heart failure are at risk from thromboembolic events originating from both arterial and venous circulation [9, 10]. This is likely, in part, a result of the fact that the syndrome of heart failure fulfills Virchow’s triad of risk factors for thrombus formation: (1) endothelial injury or dysfunction due to dilation and scarring of the cardiac chambers and associated changes in the peripheral vascular bed; (2) turbulence or stasis of blood flow in the cardiac chambers and peripheral veins secondary to myocardial contractile dysfunction, low cardiac output and/or myocardial aneurysms; and (3) hypercoagulability as a result of platelet dysfunction and an increase in thrombin and fibrinolytic activity [11–13]. Recent estimates suggest that baseline annual stroke risk increases with severity of NYHA functional class: 0.5 % for mild, 1.5 % for moderate and up to 4 % for severe heart failure [14]. The most effective strategy for stroke prevention in this population of heart failure patients in sinus rhythm primarily involves aggressive risk factor modification (i.e., blood pressure and diabetes control). While earlier retrospective studies such as the PROMISE [10] and SOLVD [15] trials suggested that anticoagulation with warfarin might be an effective stroke prevention strategy for patients with heart failure and sinus rhythm, the retrospective analysis of V-HeFT I and II [16] did not find that warfarin decreased the incidence of stroke in this population. The prospective WARCEF trial [17], which evaluated whether warfarin or aspirin treatment, had differential effects on the combined primary endpoint of ischemic stroke, intracerebral hemorrhage or death from any cause also provided mixed results. They found that while warfarin treatment was associated with a significantly decreased risk of ischemic stroke as compared to aspirin, there was a concomitant increased risk of major bleeding in the warfarin group, although the rates of intracerebral and intracranial hemorrhage were not different. A recommendation for use of warfarin for stroke prevention in all patients with heart failure and sinus rhythm cannot be made at this time.
Stroke risk in patients with heart failure and atrial fibrillation Atrial fibrillation increases thromboembolic risk in heart failure, presumably in part by causing chaotic contraction of the cardiac atria. This uncoordinated atrial contraction probably increases atrial thrombi formation, fulfilling at least the first two components of Virchow’s triad: endothelial injury (secondary to dilation and fibrotic changes in
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the left atrium) and circulatory stasis (frequently in the left atrial appendage). Many scoring systems have been developed to predict stroke risk in atrial fibrillation, including the AF Investigators (AFI) [18], Stroke Prevention in AF (SPAF) [19], CHADS2 [20], Framingham [21] and CHA2DS2-VASc [22]. The most widely used score—the CHADS2 score [congestive heart failure (C), hypertension (H), age C 75 (A), diabetes (D), and stroke or transient ischemic attack (TIA) (S2)]—was developed from a combination of the AFI and SPAF stroke risk schemes and was validated using the National Registry of AF (NRAF), which consisted of approximately 1,700 Medicare beneficiaries with nonrheumatic AF who were not anticoagulated with warfarin at hospital discharge [20]. While each of the first four risk factors receives 1 point, prior stroke or TIA receives two points, with higher scores corresponding to an increased risk of stroke. The original Gage et al. [20] study found that while a CHADS2 score of 0 is correlated with an adjusted annual stroke rate of 1.9 %, a score of C4 is correlated with a rate of [8.5 %. However, since its publication, there have been slightly lower estimates, likely based on the co-morbidities of the populations studied. Fang et al. [23], in an analysis of the ATRIA cohort of 10,932 individuals with non-valvular atrial fibrillation (both inpatients and outpatients) who were not on warfarin, found annual stroke rates to be lower: approximately 0.5 % for CHADS2 score of 0, 2.2 % for a CHADS2 score of 1 or 2 and [3 % for a CHADS2 score of C3. Similarly, a retrospective analysis of the WHI cohort of ambulatory post-menopausal women found annualized stroke risk to be 0.36, 0.72, 1.27, 1.45 and 2.43 % for CHADS2 scores 0, 1, 2, 3 and C4, respectively [24]. Although the CHADS2 score has proven to be a very useful risk stratification scheme, one of its weaknesses is that it places a large percentage of patients (up to 48 % by some estimates) [25] in an intermediate risk category (CHADS2 = 1). As a solution to this, an expansion of the CHADS2 score—the CHA2DS2-VASc score [22]—has been developed more recently in order to help further risk stratify low and intermediate risk patients with CHADS2 scores of 0 or 1. It adds four additional elements to the original CHADS2 score: (1) age between 65 and 74 years (A); (2) vascular disease (defined as prior myocardial infarction, peripheral arterial disease or aortic plaque) (V); (3) female sex (S); and (4) stroke, which was expanded to include a history of systemic thromboembolism (S2). All risk factors receive 1 point, except age C 75 and history of prior stroke/TIA/thromboembolism, which receive two points each. It is a modification of the 2006 Birmingham/ NICE stroke risk stratification scheme [26] and was validated using a cohort of 1,084 hospitalized, ambulatory
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patients who were not anticoagulated at baseline from the Euro Heart Survey on AF [22]. While both the CHADS2 and CHA2DS2-VASc scores include heart failure as a risk factor for stroke in patients with atrial fibrillation, what is less clear is how to define heart failure in this context. The original CHADS2 study defined heart failure as a recent ‘‘index hospitalization that carried the principle diagnosis of [congestive heart failure]’’ [20]. Lip et al.’s [22] validation of the CHA2DS2VASc score defined heart failure in clinical terms or if there was evidence of left ventricular dysfunction. Despite the emphasis on myocardial contractile dysfunction as a contributor to thromboembolic risk, there is some evidence that stroke risk is similar for heart failure patients with atrial fibrillation whether they have preserved or depressed left ventricular function [6, 27]. Because many patients with heart failure have devices such as pacemakers, defibrillators and cardiac resynchronization therapy, clinicians are given access to information about an individual patient’s heart rhythm trends around the clock and the cardiac devices pick up silent AF episodes both of short duration and even long episodes. A recent study evaluated the association between silent or subclinical atrial tachyarrhythmias detected by pacemaker in a population without prior history of atrial fibrillation and the occurrence of both clinical atrial fibrillation and ischemic stroke or systemic embolism. The study found that the presence of episodes of atrial rate [190 beats per minute for more than 6 min correlated with both [28]. However, this study does not provide guidance for a threshold atrial tachyarrhythmia burden beyond which anticoagulation would be recommended if a patient was thought to be at high risk for stroke. The issue of atrial fibrillation burden also comes up in the context of treatment for patients after they have received percutaneous or surgical ablation of atrial fibrillation. If we look to evidence from the antiarrhythmic rhythm control literature, while a recent observational study found a lower rate of stroke or TIA in a population of patients treated with rhythm control, as compared with patients treated with rate control [29], a recent meta-analysis of ten randomized-controlled trials demonstrated that rate control and rhythm control strategies do not differ in incidence of stroke or TIA [30]. Pathophysiologically, the likely reason for this is that patients have frequent asymptomatic episodes of atrial fibrillation that still provide the substrate for thromboembolic events. Nonetheless, in the atrial fibrillation ablation literature, a recent observational study comparing patients after atrial fibrillation ablation with a matched cohort treated medically found that freedom from atrial fibrillation was a powerful predictor of thromboembolic risk—although patients in this study were anticoagulated after their ablation based on their risk
factors and regardless of their rhythm [31]. In the surgical literature, while there is some retrospective evidence for a relatively low incidence of stroke after a Cox maze procedure [32], this remains to be replicated in a prospective trial. Clearly, prior to being able to recommend discontinuation of anticoagulation after a successful ablation procedure, randomized studies will need to evaluate the most appropriate approach to anticoagulation in this context. While a rare, low-risk patient may be told that they may stop anticoagulation in favor of aspirin alone if no recurrent atrial fibrillation has been documented in the months after the surgery, this approach is not yet broadly applicable.
National guidelines for stroke risk stratification The major cardiovascular societies in the USA (Fig. 1) [33], Europe (Fig. 2) [34] and Canada (Fig. 3) [35] have published guidelines for stroke risk stratification and anticoagulation in the context of atrial fibrillation. They all recognize heart failure as a risk factor for stroke but the USA and Canadian guidelines do not define heart failure. Only the European guidelines specifically define heart failure as severe systolic dysfunction or recent hospitalization for decompensated heart failure irrespective of ejection fraction.
Stroke prevention options To prevent embolic stroke, patients with heart failure and atrial fibrillation should be considered as potential candidates for anticoagulation. There is moderate evidence from randomized trials that aspirin treatment reduces risk of stroke compared to placebo. Atrial Fibrillation Investigators study pooled data from five studies that evaluated the efficacy of aspirin and warfarin, roughly 20 % of whom had heart failure [36]. The study reported that aspirin reduces the risk of stroke in AF by about 20 %. The ACTIVE trial demonstrated that addition of clopidogrel to aspirin further decreased stoke risk by 27 %. However, the benefit was offset by an almost twofold increased risk of major hemorrhage. Overall, there is little evidence for use of antiplatelet agents for stroke reduction in patients with atrial fibrillation and heart failure. Until recently, warfarin and other vitamin K antagonists were the mainstay for stroke prevention in atrial fibrillation. In 2007, Hart et al. [37] published a definitive metaanalysis of 29 randomized trials evaluating the effect of warfarin and antiplatelet therapy on risk of stroke in atrial fibrillation. When the findings of the individual studies
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Fig. 1 American College of Cardiology/American Heart Association/Heart Rhythm Society: stroke risk stratification in atrial fibrillation
were merged into three groups—(1) warfarin versus placebo or control, (2) antiplatelet therapy versus placebo or control and (3) warfarin versus antiplatelet therapy—they found that compared to placebo or control, warfarin provided a 64 % decreased risk of stroke, antiplatelet therapy provided a 22 % decreased risk of stroke and that compared to antiplatelet therapy, warfarin decreased the risk of stroke by 39 %. After almost 20 years of having warfarin as the only agent for oral anticoagulation, the RE-LY (dabigatran, a direct thrombin inhibitor) [38] ROCKET AF (rivaroxaban, a direct factor Xa inhibitor) [39], AVERROES (apixaban, a direct factor Xa inhibitor) [40] and ARISTOTLE (apixaban) [41] trials have provided support for the use of new agents that do not require the frequent monitoring and food restrictions required by warfarin treatment. These trials have given the medical community information regarding the safety, efficacy and bleeding risks of each of these new drugs as well as additional information about aspirin and warfarin. The RE-LY trial (2009) [42] evaluated the safety and efficacy of dabigatran (at two different dosages) compared to adjusted-dose warfarin in a population with non-valvular atrial fibrillation with at least one of the following risk factors: prior stroke or TIA, history of heart failure, age of at least 75 or age between 65 and 74 plus diabetes mellitus, hypertension or coronary artery disease. Approximately 32 % of the RE-LY patient population had heart failure, where heart failure was defined as left ventricular ejection fraction less than 40 % or NYHA class II or higher heart failure symptoms in the previous 6 months. While dabigatran 110 mg bid was non-inferior to warfarin in prevention of stroke and systemic embolism prevention (1.53 vs. 1.69 % per year, respectively) and was associated with
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significantly lower rates of major hemorrhage (2.71 vs. 3.36 % per year, respectively), dabigatran 150 mg bid was significantly superior to warfarin in preventing stroke and systemic embolism (1.11 vs. 1.69 % per year, respectively) but had similar rates of major hemorrhage compared to warfarin (3.11 vs. 3.36 % per year, respectively). The ROCKET AF trial (2011) [39] evaluated the safety and efficacy of rivaroxaban compared to adjusted-dose warfarin in a population with non-valvular atrial fibrillation with a CHADS2 score of at least two. Approximately 62 % of the ROCKET AF patient population had heart failure, where heart failure was defined as left ventricular ejection fraction less than or equal to 35 % or heart failure symptoms. They found that rivaroxaban 20 mg daily was noninferior to warfarin in prevention of stroke and systemic embolism prevention (1.7 vs. 2.2 % per year, as treated and 2.1 vs. 2.4 % per year, intention-to-treat, respectively) and was associated with significantly lower rates of critical bleeding (1.3 vs. 1.9 % per year, respectively). ARISTOTLE (2011) [41] evaluated the safety and efficacy of apixaban compared to adjusted-dose warfarin in a population with non-valvular atrial fibrillation or atrial flutter with a CHADS2 score of at least one. Approximately 35 % of the ARISTOTLE patient population had heart failure, where heart failure was defined as left ventricular ejection fraction less than or equal to 40 % or symptomatic heart failure within the prior 3 months. They found that apixaban 5 mg twice daily was superior to warfarin in prevention of stroke and systemic embolism prevention (1.27 vs. 1.60 % per year, respectively) and was associated with significantly lower rates of major bleeding (2.13 vs. 3.09 % per year, respectively). AVERROES (2011) [40] evaluated the safety and efficacy of apixaban compared to aspirin in a population with
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that apixaban 5 mg twice daily was superior to aspirin 81–324 mg daily in prevention of stroke and systemic embolism prevention (1.6 vs. 3.7 % per year, respectively) and was associated with similar rates of major bleeding (1.4 vs. 1.2 % per year, respectively). This trial was terminated early due to clear benefit in favor of apixaban although there is new evidence that upon discontinuation of the drug, patients may be pro-thrombotic and thus at increased risk of stroke and that if this is planned, they should be bridged with alternative anticoagulation [43]. Although no trial has compared the available oral anticoagulants in a heart failure population, because a significant number of the patients in each of the above trials had a diagnosis of heart failure, it seems reasonable to use these newer agents in the heart failure population with atrial fibrillation and risk factors for stroke. However, one caveat is that a significant percentage of heart failure patients have some degree of renal insufficiency, and while warfarin may be used in patients across all levels of renal function, the dosing of the three new oral anticoagulants must be adjusted for renal insufficiency [43]. Dabigatran dosing is modified for creatinine clearance of 15–30 ml/min (75 mg bid), rivaroxaban is dosed at 15 mg daily for creatinine clearance of 15–50 ml/min, apixaban is dosed at 2.5 mg twice daily if a patient has two or more of the following: age greater than or equal to 80 years, serum creatinine greater than or equal to 1.5 or body weight less than or equal to 60 kg. None of the three new oral anticoagulants may be used with a creatinine clearance of less than or equal to 15 ml/min or in patients on hemodialysis.
Bleeding risk assessment
Fig. 2 European Society of Cardiology: stroke risk stratification in atrial fibrillation
atrial fibrillation for whom warfarin therapy was unsuitable who were at least 50 years old with at least one of the following risk factors for stroke: prior stroke or TIA, age greater than or equal to 75, hypertension requiring treatment, diabetes mellitus requiring treatment, heart failure or peripheral artery disease. Approximately 39 % of the AVERROES patient population had heart failure, where heart failure was defined as left ventricular ejection fraction less than or equal to 35 % or NYHA class II or higher heart failure symptoms at the time of enrollment. They found
Given the elevated risk of bleeding associated with all pharmacologic approaches to stroke prevention, several risk scores have been developed to assist in bleeding risk assessment: HEMORR2HAGES [44], Shireman [45], HAS-BLED [46] and ATRIA [47]. As summarized in Table 1, many of the risk factors that increase risk of stroke—such as increasing age, hypertension, prior stroke and history of diabetes—are associated with bleeding risk as well. Nonetheless, several unique factors seem be predictive in several of the models—history of hepatic or renal disease, anemia, alcohol or drug abuse and history of bleeding. For instance, the most recent of these, the ATRIA risk score for assessment of bleeding risk on warfarin, found that anemia (three points), GFR \ 30 ml/min or hemodialysis (three points), age C 75 years (two points), prior bleeding history (one point) and hypertension (one point) were all predictive of risk of major bleeding. In the ATRIA cohort of [13,000 patients with non-valvular atrial fibrillation who were enrolled in the Kaiser Permanente
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Heart Fail Rev Fig. 3 Canadian Cardiovascular Society: stroke risk stratification in atrial fibrillation. ASA acetylsalicylic acid (aspirin), OAC oral anticoagulant
medical system in Northern California, risk of major bleeding varied from B1 % per year in low-risk individuals (0–3 points) to [5 % per year in high-risk individuals (5–10 points). Bleeding risk assessment is particularly relevant to individuals with heart failure as many of them will have some degree of renal or liver disease, anemia and bleeding history. Clearly, heart failure patients with atrial fibrillation should be evaluated on a case-by-case basis, taking into consideration a patient’s unique risk profile as well as preference in order to weigh the risks and benefits of anticoagulation. Also, while the bleeding risk scores provide guidance for patients who will be treated with warfarin, we do not yet have risk scores that assess relative bleeding risk on the new oral anticoagulants. A widely mentioned risk factor relevant to the heart failure population is fall risk. While clinicians generally take fall risk into consideration when making decisions regarding anticoagulation, it is interesting to note that a 1999 Markov model that evaluated the preferred stroke prevention strategy for elderly patients with atrial fibrillation came to the opposite conclusion [48]. Further, while the ATRIA cohort found that fall risk was a statistically significant although weaker predictor of bleeding risk, only HEMORR2HAGES included it explicitly as a risk factor. Neither Shireman et al. nor HAS-BLED evaluated fall risk in their cohorts. Overall, it appears that this topic deserves further evaluation, particularly in the current era of new oral anticoagulants.
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Left atrial appendage occlusion Although not yet first line for stroke prevention, left atrial appendage (LAA) closure or ligation—either percutaneously or at the time of open heart surgery—is an option for those patients at high risk of stroke and whose bleeding risk on an oral anticoagulant is prohibitively high [49]. However, the stroke outcome data for surgical LAA ligation are limited, the Watchman device (the only FDA approved percutaneous LAA occlusion device) requires antiplatelet treatment and the LARIAT device that occludes the LAA via an epicardial snare is still in clinical trials and will be available only to patients in whom percutaneous epicardial access is possible.
Future directions Stroke risk stratification and anticoagulation for patients with atrial fibrillation and heart failure is an evolving field. In terms of future directions, we look forward to the publication of registries that include more ‘‘real-life’’ patients with atrial fibrillation and heart failure on the new oral anticoagulants to determine whether the outcomes match those of the clinical trials in terms of stroke prevention and bleeding risk in addition to providing comparative data across agents. This is particularly important in light of the call for a FDA Mini-Sentinel analysis of insurance claim data to evaluate bleeding rates for dabigatran and warfarin
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References
9f
9d
GFR \ 30 ml/min or on hemodialysis
C75 years f
e
Antiplatelet use
[65 years d
c
[75 years C70 years
9e ATRIA
b
9 HAS-BLED
a
9
9 Shireman
HEMORR2HAGES
9
9
9
9
b
9
c
9 9a
9
9 9
9 9
Conflict of interest JoEllyn M. Abraham: None. Stuart J. Connolly: Honoraria for lectures and consulting for Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Sanofi Aventis, Portola, Bayer and Johnson and Johnson.
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Diabetes History of Bleeding Female Gender Prior Stroke Fall risk Genetic factors Anemia HTN Reduced platelet count/function Age Malignancy Alcohol/ drug abuse Hepatic or renal disease
Table 1 Bleeding risk scores
(the rates were similar in the analysis) [50]. In addition, given that the recently published RELY-ABLE study (an observational extension of the RELY patients that continued on dabigatran at study end with blinding to dose strength) suggested that the 110 and 150 mg twice daily dosages had equivalent rates of stroke and death with increased major bleeding in the 150 mg group, clearly more data are required to elucidate this issue [51]. Further, because there is evidence for significant underutilization of appropriate anticoagulation in the context of the warfarin only era (only 42 % of patients with CHADS2 scores of C3 were anticoagulated in one cohort) [52], it will be important to continue to evaluate this issue now that alternative options are available. Lastly, more evidence is needed to guide when to offer anticoagulation to heart failure patients with devices that detect brief episodes of atrial fibrillation.
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25. Conen D, Chae CU, Glynn RJ, Tedrow UB, Everett BM, Buring JE, Albert CM (2011) Risk of death and cardiovascular events in initially healthy women with new-onset atrial fibrillation. J Am Med Assoc 305(20):2080–2087 26. NICE (2006) In: National Health Service NCCfCC (ed) NICE clinical guideline 36: the management of atrial fibrillation. National Institute for Health and Clinical Excellence 27. Banerjee A, Taillandier S, Olesen JB, Lane DA, Lallemand B, Lip GY, Fauchier L (2012) Ejection fraction and outcomes in patients with atrial fibrillation and heart failure: the Loire Valley Atrial Fibrillation Project. Eur J Heart Fail 14(3):295–301 28. Healey JS, Connolly SJ, Gold MR, Israel CW, Van Gelder IC, Capucci A, Lau CP, Fain E, Yang S, Bailleul C et al (2012) Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 366(2):120–129 29. Tsadok MA, Jackevicius CA, Essebag V, Eisenberg MJ, Rahme E, Humphries KH, Tu JV, Behlouli H, Pilote L (2012) Rhythm versus rate control therapy and subsequent stroke or transient ischemic attack in patients with atrial fibrillation. Circulation 126(23):2680–2687 30. Chatterjee S, Sardar P, Lichstein E, Mukherjee D, Aikat S (2013) Pharmacologic rate versus rhythm-control strategies in atrial fibrillation: an updated comprehensive review and meta-analysis. Pacing Clin Electrophysiol 36(1):122–133 31. Hunter RJ, McCready J, Diab I, Page SP, Finlay M, Richmond L, French A, Earley MJ, Sporton S, Jones M et al (2012) Maintenance of sinus rhythm with an ablation strategy in patients with atrial fibrillation is associated with a lower risk of stroke and death. Heart 98(1):48–53 32. Pet M, Robertson JO, Bailey M, Guthrie TJ, Moon MR, Lawton JS, Rinne A, Damiano RJ Jr, Maniar HS (2013) The impact of CHADS(2) score on late stroke after the Cox maze procedure. J Thorac Cardiovasc Surg 146:85–89 33. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Huezey JY, Lowe JE et al (2011) 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol 57(11):e101–e198 34. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B et al (2010) Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 31(19): 2369–2429 35. Skanes AC, Healey JS, Cairns JA, Dorian P, Gillis AM, McMurtry MS, Mitchell LB, Verma A, Nattel S (2012) Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 28(2):125–136 36. The Atrial Fibrillation Investigators (1994) Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 154(13):1449–1457 37. Hart RG, Pearce LA, Aguilar MI (2007) Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 146(12):857–867 38. Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J et al (2010) Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for
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46. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY (2010) A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 138(5):1093–1100 47. Fang MC, Go AS, Chang Y, Borowsky LH, Pomernacki NK, Udaltsova N, Singer DE (2011) A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol 58(4):395–401 48. Man-Son-Hing M, Nichol G, Lau A, Laupacis A (1999) Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med 159(7):677–685 49. Syed FF, Asirvatham SJ (2011) Left atrial appendage as a target for reducing strokes: justifiable rationale? Safe and effective approaches? Heart Rhythm 8(2):194–198 50. Southworth MR, Reichman ME, Unger EF (2013) Dabigatran and postmarketing reports of bleeding. N Engl J Med 368(14): 1272–1274 51. Connolly SJ, Wallentin L, Ezekowitz MD, Eikelboom J, Oldgren J, Reilly PA, Brueckmann M, Pogue J, Alings M, Amerena JV et al (2013) The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELYABLE) Study. Circulation 128(3):237–243 52. Zimetbaum PJ, Thosani A, Yu HT, Xiong Y, Lin J, Kothawala P, Emons M (2010) Are atrial fibrillation patients receiving warfarin in accordance with stroke risk? Am J Med 123(5):446–453
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Atrial fibrillation in heart failure: stroke risk stratification and anticoagulation JoEllyn M. Abraham • Stuart J. Connolly
Ó Springer Science+Business Media New York 2014
Abstract For an individual patient with both atrial fibrillation and heart failure, stroke risk is one of the most prominent mitigating factors for subsequent morbidity and mortality. Although the CHADS2 stroke risk score is the most widely used score for risk stratification, it does not take into account the risk factors of vascular disease, female gender, or the age group 65–74 years, for which there is increasing evidence. There is also evidence that diastolic heart failure is as much a risk factor for stroke as systolic heart failure. The new oral anticoagulants dabigatran, rivaroxaban and apixaban appear to be appropriate agents in the heart failure population with atrial fibrillation and risk factors for stroke although there are dose-adjustments for renal insufficiency and these medications are contraindicated in advanced renal disease. As with the atrial fibrillation population as a whole, bleeding risk should be considered for every patient with heart failure prior to making recommendations regarding anticoagulation. Keywords Heart failure Atrial fibrillation Stroke Anticoagulation
Epidemiology of heart failure and atrial fibrillation Heart failure and atrial fibrillation are diagnoses that frequently co-exist in the same population. Indeed, of those
J. M. Abraham (&) Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, J2-2, Cleveland, OH 44195, USA e-mail: [email protected] S. J. Connolly Division of Cardiology, McMaster University, Hamilton, Canada
with a diagnosis of atrial fibrillation, about 40 % will develop a concomitant diagnosis of heart failure and the reverse is true as well [1, 2]. Most recent estimates suggest that there are 2.7 million individuals with atrial fibrillation in the USA, with a prevalence of 0.5 % in individuals younger than 60 years old and 8.8 % in octogenarians and those older (overall prevalence approximately 1 %). Further, atrial fibrillation is more common in men than women (1.1 vs. 0.8 % overall prevalence and 3 vs. 1.7 % in patients aged 65–69) [3, 4]. The prevalence of heart failure in the USA is even higher, with the disease affecting roughly 5.1 million individuals (approximately 2 % of the population) [2, 4]. The prevalence of atrial fibrillation increases with increasing New York Heart Association (NYHA) Class, and it appears to be similar for heart failure with both preserved and reduced systolic function [5, 6]. For both conditions, the prevalence is projected to continue to increase in the foreseeable future [4]. For an individual patient with both atrial fibrillation and heart failure, stoke prevention is an important medical concern. About 15 % of strokes in the USA are thought to be caused by atrial fibrillation [3]. It is important to emphasize that while thromboembolism is the most common cause for stroke in the population with atrial fibrillation, up to 25 % of strokes in this population occur secondary to other etiologies such as aortic and carotid atherosclerotic disease and microvascular disease from underlying hypertension [7, 8]. This statistic underscores the importance of risk factor modification for this population when making assessments of embolic stroke risk. This review article will aim to cover some of the unique challenges of assessing risk of stroke as well as those of deriving safe and effective stroke prevention strategies in patients with both of these comorbidities.
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Stroke risk in patients with heart failure and sinus rhythm It has long been recognized that patients with heart failure are at risk from thromboembolic events originating from both arterial and venous circulation [9, 10]. This is likely, in part, a result of the fact that the syndrome of heart failure fulfills Virchow’s triad of risk factors for thrombus formation: (1) endothelial injury or dysfunction due to dilation and scarring of the cardiac chambers and associated changes in the peripheral vascular bed; (2) turbulence or stasis of blood flow in the cardiac chambers and peripheral veins secondary to myocardial contractile dysfunction, low cardiac output and/or myocardial aneurysms; and (3) hypercoagulability as a result of platelet dysfunction and an increase in thrombin and fibrinolytic activity [11–13]. Recent estimates suggest that baseline annual stroke risk increases with severity of NYHA functional class: 0.5 % for mild, 1.5 % for moderate and up to 4 % for severe heart failure [14]. The most effective strategy for stroke prevention in this population of heart failure patients in sinus rhythm primarily involves aggressive risk factor modification (i.e., blood pressure and diabetes control). While earlier retrospective studies such as the PROMISE [10] and SOLVD [15] trials suggested that anticoagulation with warfarin might be an effective stroke prevention strategy for patients with heart failure and sinus rhythm, the retrospective analysis of V-HeFT I and II [16] did not find that warfarin decreased the incidence of stroke in this population. The prospective WARCEF trial [17], which evaluated whether warfarin or aspirin treatment, had differential effects on the combined primary endpoint of ischemic stroke, intracerebral hemorrhage or death from any cause also provided mixed results. They found that while warfarin treatment was associated with a significantly decreased risk of ischemic stroke as compared to aspirin, there was a concomitant increased risk of major bleeding in the warfarin group, although the rates of intracerebral and intracranial hemorrhage were not different. A recommendation for use of warfarin for stroke prevention in all patients with heart failure and sinus rhythm cannot be made at this time.
Stroke risk in patients with heart failure and atrial fibrillation Atrial fibrillation increases thromboembolic risk in heart failure, presumably in part by causing chaotic contraction of the cardiac atria. This uncoordinated atrial contraction probably increases atrial thrombi formation, fulfilling at least the first two components of Virchow’s triad: endothelial injury (secondary to dilation and fibrotic changes in
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the left atrium) and circulatory stasis (frequently in the left atrial appendage). Many scoring systems have been developed to predict stroke risk in atrial fibrillation, including the AF Investigators (AFI) [18], Stroke Prevention in AF (SPAF) [19], CHADS2 [20], Framingham [21] and CHA2DS2-VASc [22]. The most widely used score—the CHADS2 score [congestive heart failure (C), hypertension (H), age C 75 (A), diabetes (D), and stroke or transient ischemic attack (TIA) (S2)]—was developed from a combination of the AFI and SPAF stroke risk schemes and was validated using the National Registry of AF (NRAF), which consisted of approximately 1,700 Medicare beneficiaries with nonrheumatic AF who were not anticoagulated with warfarin at hospital discharge [20]. While each of the first four risk factors receives 1 point, prior stroke or TIA receives two points, with higher scores corresponding to an increased risk of stroke. The original Gage et al. [20] study found that while a CHADS2 score of 0 is correlated with an adjusted annual stroke rate of 1.9 %, a score of C4 is correlated with a rate of [8.5 %. However, since its publication, there have been slightly lower estimates, likely based on the co-morbidities of the populations studied. Fang et al. [23], in an analysis of the ATRIA cohort of 10,932 individuals with non-valvular atrial fibrillation (both inpatients and outpatients) who were not on warfarin, found annual stroke rates to be lower: approximately 0.5 % for CHADS2 score of 0, 2.2 % for a CHADS2 score of 1 or 2 and [3 % for a CHADS2 score of C3. Similarly, a retrospective analysis of the WHI cohort of ambulatory post-menopausal women found annualized stroke risk to be 0.36, 0.72, 1.27, 1.45 and 2.43 % for CHADS2 scores 0, 1, 2, 3 and C4, respectively [24]. Although the CHADS2 score has proven to be a very useful risk stratification scheme, one of its weaknesses is that it places a large percentage of patients (up to 48 % by some estimates) [25] in an intermediate risk category (CHADS2 = 1). As a solution to this, an expansion of the CHADS2 score—the CHA2DS2-VASc score [22]—has been developed more recently in order to help further risk stratify low and intermediate risk patients with CHADS2 scores of 0 or 1. It adds four additional elements to the original CHADS2 score: (1) age between 65 and 74 years (A); (2) vascular disease (defined as prior myocardial infarction, peripheral arterial disease or aortic plaque) (V); (3) female sex (S); and (4) stroke, which was expanded to include a history of systemic thromboembolism (S2). All risk factors receive 1 point, except age C 75 and history of prior stroke/TIA/thromboembolism, which receive two points each. It is a modification of the 2006 Birmingham/ NICE stroke risk stratification scheme [26] and was validated using a cohort of 1,084 hospitalized, ambulatory
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patients who were not anticoagulated at baseline from the Euro Heart Survey on AF [22]. While both the CHADS2 and CHA2DS2-VASc scores include heart failure as a risk factor for stroke in patients with atrial fibrillation, what is less clear is how to define heart failure in this context. The original CHADS2 study defined heart failure as a recent ‘‘index hospitalization that carried the principle diagnosis of [congestive heart failure]’’ [20]. Lip et al.’s [22] validation of the CHA2DS2VASc score defined heart failure in clinical terms or if there was evidence of left ventricular dysfunction. Despite the emphasis on myocardial contractile dysfunction as a contributor to thromboembolic risk, there is some evidence that stroke risk is similar for heart failure patients with atrial fibrillation whether they have preserved or depressed left ventricular function [6, 27]. Because many patients with heart failure have devices such as pacemakers, defibrillators and cardiac resynchronization therapy, clinicians are given access to information about an individual patient’s heart rhythm trends around the clock and the cardiac devices pick up silent AF episodes both of short duration and even long episodes. A recent study evaluated the association between silent or subclinical atrial tachyarrhythmias detected by pacemaker in a population without prior history of atrial fibrillation and the occurrence of both clinical atrial fibrillation and ischemic stroke or systemic embolism. The study found that the presence of episodes of atrial rate [190 beats per minute for more than 6 min correlated with both [28]. However, this study does not provide guidance for a threshold atrial tachyarrhythmia burden beyond which anticoagulation would be recommended if a patient was thought to be at high risk for stroke. The issue of atrial fibrillation burden also comes up in the context of treatment for patients after they have received percutaneous or surgical ablation of atrial fibrillation. If we look to evidence from the antiarrhythmic rhythm control literature, while a recent observational study found a lower rate of stroke or TIA in a population of patients treated with rhythm control, as compared with patients treated with rate control [29], a recent meta-analysis of ten randomized-controlled trials demonstrated that rate control and rhythm control strategies do not differ in incidence of stroke or TIA [30]. Pathophysiologically, the likely reason for this is that patients have frequent asymptomatic episodes of atrial fibrillation that still provide the substrate for thromboembolic events. Nonetheless, in the atrial fibrillation ablation literature, a recent observational study comparing patients after atrial fibrillation ablation with a matched cohort treated medically found that freedom from atrial fibrillation was a powerful predictor of thromboembolic risk—although patients in this study were anticoagulated after their ablation based on their risk
factors and regardless of their rhythm [31]. In the surgical literature, while there is some retrospective evidence for a relatively low incidence of stroke after a Cox maze procedure [32], this remains to be replicated in a prospective trial. Clearly, prior to being able to recommend discontinuation of anticoagulation after a successful ablation procedure, randomized studies will need to evaluate the most appropriate approach to anticoagulation in this context. While a rare, low-risk patient may be told that they may stop anticoagulation in favor of aspirin alone if no recurrent atrial fibrillation has been documented in the months after the surgery, this approach is not yet broadly applicable.
National guidelines for stroke risk stratification The major cardiovascular societies in the USA (Fig. 1) [33], Europe (Fig. 2) [34] and Canada (Fig. 3) [35] have published guidelines for stroke risk stratification and anticoagulation in the context of atrial fibrillation. They all recognize heart failure as a risk factor for stroke but the USA and Canadian guidelines do not define heart failure. Only the European guidelines specifically define heart failure as severe systolic dysfunction or recent hospitalization for decompensated heart failure irrespective of ejection fraction.
Stroke prevention options To prevent embolic stroke, patients with heart failure and atrial fibrillation should be considered as potential candidates for anticoagulation. There is moderate evidence from randomized trials that aspirin treatment reduces risk of stroke compared to placebo. Atrial Fibrillation Investigators study pooled data from five studies that evaluated the efficacy of aspirin and warfarin, roughly 20 % of whom had heart failure [36]. The study reported that aspirin reduces the risk of stroke in AF by about 20 %. The ACTIVE trial demonstrated that addition of clopidogrel to aspirin further decreased stoke risk by 27 %. However, the benefit was offset by an almost twofold increased risk of major hemorrhage. Overall, there is little evidence for use of antiplatelet agents for stroke reduction in patients with atrial fibrillation and heart failure. Until recently, warfarin and other vitamin K antagonists were the mainstay for stroke prevention in atrial fibrillation. In 2007, Hart et al. [37] published a definitive metaanalysis of 29 randomized trials evaluating the effect of warfarin and antiplatelet therapy on risk of stroke in atrial fibrillation. When the findings of the individual studies
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Fig. 1 American College of Cardiology/American Heart Association/Heart Rhythm Society: stroke risk stratification in atrial fibrillation
were merged into three groups—(1) warfarin versus placebo or control, (2) antiplatelet therapy versus placebo or control and (3) warfarin versus antiplatelet therapy—they found that compared to placebo or control, warfarin provided a 64 % decreased risk of stroke, antiplatelet therapy provided a 22 % decreased risk of stroke and that compared to antiplatelet therapy, warfarin decreased the risk of stroke by 39 %. After almost 20 years of having warfarin as the only agent for oral anticoagulation, the RE-LY (dabigatran, a direct thrombin inhibitor) [38] ROCKET AF (rivaroxaban, a direct factor Xa inhibitor) [39], AVERROES (apixaban, a direct factor Xa inhibitor) [40] and ARISTOTLE (apixaban) [41] trials have provided support for the use of new agents that do not require the frequent monitoring and food restrictions required by warfarin treatment. These trials have given the medical community information regarding the safety, efficacy and bleeding risks of each of these new drugs as well as additional information about aspirin and warfarin. The RE-LY trial (2009) [42] evaluated the safety and efficacy of dabigatran (at two different dosages) compared to adjusted-dose warfarin in a population with non-valvular atrial fibrillation with at least one of the following risk factors: prior stroke or TIA, history of heart failure, age of at least 75 or age between 65 and 74 plus diabetes mellitus, hypertension or coronary artery disease. Approximately 32 % of the RE-LY patient population had heart failure, where heart failure was defined as left ventricular ejection fraction less than 40 % or NYHA class II or higher heart failure symptoms in the previous 6 months. While dabigatran 110 mg bid was non-inferior to warfarin in prevention of stroke and systemic embolism prevention (1.53 vs. 1.69 % per year, respectively) and was associated with
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significantly lower rates of major hemorrhage (2.71 vs. 3.36 % per year, respectively), dabigatran 150 mg bid was significantly superior to warfarin in preventing stroke and systemic embolism (1.11 vs. 1.69 % per year, respectively) but had similar rates of major hemorrhage compared to warfarin (3.11 vs. 3.36 % per year, respectively). The ROCKET AF trial (2011) [39] evaluated the safety and efficacy of rivaroxaban compared to adjusted-dose warfarin in a population with non-valvular atrial fibrillation with a CHADS2 score of at least two. Approximately 62 % of the ROCKET AF patient population had heart failure, where heart failure was defined as left ventricular ejection fraction less than or equal to 35 % or heart failure symptoms. They found that rivaroxaban 20 mg daily was noninferior to warfarin in prevention of stroke and systemic embolism prevention (1.7 vs. 2.2 % per year, as treated and 2.1 vs. 2.4 % per year, intention-to-treat, respectively) and was associated with significantly lower rates of critical bleeding (1.3 vs. 1.9 % per year, respectively). ARISTOTLE (2011) [41] evaluated the safety and efficacy of apixaban compared to adjusted-dose warfarin in a population with non-valvular atrial fibrillation or atrial flutter with a CHADS2 score of at least one. Approximately 35 % of the ARISTOTLE patient population had heart failure, where heart failure was defined as left ventricular ejection fraction less than or equal to 40 % or symptomatic heart failure within the prior 3 months. They found that apixaban 5 mg twice daily was superior to warfarin in prevention of stroke and systemic embolism prevention (1.27 vs. 1.60 % per year, respectively) and was associated with significantly lower rates of major bleeding (2.13 vs. 3.09 % per year, respectively). AVERROES (2011) [40] evaluated the safety and efficacy of apixaban compared to aspirin in a population with
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that apixaban 5 mg twice daily was superior to aspirin 81–324 mg daily in prevention of stroke and systemic embolism prevention (1.6 vs. 3.7 % per year, respectively) and was associated with similar rates of major bleeding (1.4 vs. 1.2 % per year, respectively). This trial was terminated early due to clear benefit in favor of apixaban although there is new evidence that upon discontinuation of the drug, patients may be pro-thrombotic and thus at increased risk of stroke and that if this is planned, they should be bridged with alternative anticoagulation [43]. Although no trial has compared the available oral anticoagulants in a heart failure population, because a significant number of the patients in each of the above trials had a diagnosis of heart failure, it seems reasonable to use these newer agents in the heart failure population with atrial fibrillation and risk factors for stroke. However, one caveat is that a significant percentage of heart failure patients have some degree of renal insufficiency, and while warfarin may be used in patients across all levels of renal function, the dosing of the three new oral anticoagulants must be adjusted for renal insufficiency [43]. Dabigatran dosing is modified for creatinine clearance of 15–30 ml/min (75 mg bid), rivaroxaban is dosed at 15 mg daily for creatinine clearance of 15–50 ml/min, apixaban is dosed at 2.5 mg twice daily if a patient has two or more of the following: age greater than or equal to 80 years, serum creatinine greater than or equal to 1.5 or body weight less than or equal to 60 kg. None of the three new oral anticoagulants may be used with a creatinine clearance of less than or equal to 15 ml/min or in patients on hemodialysis.
Bleeding risk assessment
Fig. 2 European Society of Cardiology: stroke risk stratification in atrial fibrillation
atrial fibrillation for whom warfarin therapy was unsuitable who were at least 50 years old with at least one of the following risk factors for stroke: prior stroke or TIA, age greater than or equal to 75, hypertension requiring treatment, diabetes mellitus requiring treatment, heart failure or peripheral artery disease. Approximately 39 % of the AVERROES patient population had heart failure, where heart failure was defined as left ventricular ejection fraction less than or equal to 35 % or NYHA class II or higher heart failure symptoms at the time of enrollment. They found
Given the elevated risk of bleeding associated with all pharmacologic approaches to stroke prevention, several risk scores have been developed to assist in bleeding risk assessment: HEMORR2HAGES [44], Shireman [45], HAS-BLED [46] and ATRIA [47]. As summarized in Table 1, many of the risk factors that increase risk of stroke—such as increasing age, hypertension, prior stroke and history of diabetes—are associated with bleeding risk as well. Nonetheless, several unique factors seem be predictive in several of the models—history of hepatic or renal disease, anemia, alcohol or drug abuse and history of bleeding. For instance, the most recent of these, the ATRIA risk score for assessment of bleeding risk on warfarin, found that anemia (three points), GFR \ 30 ml/min or hemodialysis (three points), age C 75 years (two points), prior bleeding history (one point) and hypertension (one point) were all predictive of risk of major bleeding. In the ATRIA cohort of [13,000 patients with non-valvular atrial fibrillation who were enrolled in the Kaiser Permanente
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medical system in Northern California, risk of major bleeding varied from B1 % per year in low-risk individuals (0–3 points) to [5 % per year in high-risk individuals (5–10 points). Bleeding risk assessment is particularly relevant to individuals with heart failure as many of them will have some degree of renal or liver disease, anemia and bleeding history. Clearly, heart failure patients with atrial fibrillation should be evaluated on a case-by-case basis, taking into consideration a patient’s unique risk profile as well as preference in order to weigh the risks and benefits of anticoagulation. Also, while the bleeding risk scores provide guidance for patients who will be treated with warfarin, we do not yet have risk scores that assess relative bleeding risk on the new oral anticoagulants. A widely mentioned risk factor relevant to the heart failure population is fall risk. While clinicians generally take fall risk into consideration when making decisions regarding anticoagulation, it is interesting to note that a 1999 Markov model that evaluated the preferred stroke prevention strategy for elderly patients with atrial fibrillation came to the opposite conclusion [48]. Further, while the ATRIA cohort found that fall risk was a statistically significant although weaker predictor of bleeding risk, only HEMORR2HAGES included it explicitly as a risk factor. Neither Shireman et al. nor HAS-BLED evaluated fall risk in their cohorts. Overall, it appears that this topic deserves further evaluation, particularly in the current era of new oral anticoagulants.
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Left atrial appendage occlusion Although not yet first line for stroke prevention, left atrial appendage (LAA) closure or ligation—either percutaneously or at the time of open heart surgery—is an option for those patients at high risk of stroke and whose bleeding risk on an oral anticoagulant is prohibitively high [49]. However, the stroke outcome data for surgical LAA ligation are limited, the Watchman device (the only FDA approved percutaneous LAA occlusion device) requires antiplatelet treatment and the LARIAT device that occludes the LAA via an epicardial snare is still in clinical trials and will be available only to patients in whom percutaneous epicardial access is possible.
Future directions Stroke risk stratification and anticoagulation for patients with atrial fibrillation and heart failure is an evolving field. In terms of future directions, we look forward to the publication of registries that include more ‘‘real-life’’ patients with atrial fibrillation and heart failure on the new oral anticoagulants to determine whether the outcomes match those of the clinical trials in terms of stroke prevention and bleeding risk in addition to providing comparative data across agents. This is particularly important in light of the call for a FDA Mini-Sentinel analysis of insurance claim data to evaluate bleeding rates for dabigatran and warfarin
9
9
9 9
References
9f
9d
GFR \ 30 ml/min or on hemodialysis
C75 years f
e
Antiplatelet use
[65 years d
c
[75 years C70 years
9e ATRIA
b
9 HAS-BLED
a
9
9 Shireman
HEMORR2HAGES
9
9
9
9
b
9
c
9 9a
9
9 9
9 9
Conflict of interest JoEllyn M. Abraham: None. Stuart J. Connolly: Honoraria for lectures and consulting for Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Sanofi Aventis, Portola, Bayer and Johnson and Johnson.
9
9
9
9
9
9
Diabetes History of Bleeding Female Gender Prior Stroke Fall risk Genetic factors Anemia HTN Reduced platelet count/function Age Malignancy Alcohol/ drug abuse Hepatic or renal disease
Table 1 Bleeding risk scores
(the rates were similar in the analysis) [50]. In addition, given that the recently published RELY-ABLE study (an observational extension of the RELY patients that continued on dabigatran at study end with blinding to dose strength) suggested that the 110 and 150 mg twice daily dosages had equivalent rates of stroke and death with increased major bleeding in the 150 mg group, clearly more data are required to elucidate this issue [51]. Further, because there is evidence for significant underutilization of appropriate anticoagulation in the context of the warfarin only era (only 42 % of patients with CHADS2 scores of C3 were anticoagulated in one cohort) [52], it will be important to continue to evaluate this issue now that alternative options are available. Lastly, more evidence is needed to guide when to offer anticoagulation to heart failure patients with devices that detect brief episodes of atrial fibrillation.
9
Labile INR
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