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Comparison of Mortality and Morbidity in Patients With AtrialFibrillation and Heart Failure With Preserved Versus Decreased

Left Ventricular Ejection Fraction

Apurva O. Badheka, MDa, Ankit Rathod, MDa, Mohammad A. Kizilbash, MDb,Aditya Bhardwaj, MDa, Omaima Ali, MDa, Luis Afonso, MDa,b, and Sony Jacob, MDa,b,*

Almost 50% of patients with congestive heart failure (HF) have preserved ejection fraction(PEF). Data on the effect of HF-PEF on atrial fibrillation outcomes are lacking. Weassessed the prognostic significance of HF-PEF in an atrial fibrillation population com-pared to a systolic heart failure (SHF) population. A post hoc analysis of the NationalHeart, Lung, and Blood Institute-limited access data set of the Atrial Fibrillation Follow-upInvestigation of Rhythm Management (AFFIRM) trial was carried out. The patients witha history of congestive HF and a preserved ejection fraction (EF >50%) were classified ashaving HF-PEF (n � 320). The patients with congestive HF and a qualitatively depressedEF (EF <50%) were classified as having SHF (n � 402). Cox proportional hazards analysiswas performed. The mean follow-up duration was 1,181 � 534 days/patient. The patientswith HF-PEF had lower all-cause mortality (hazard ratio [HR] 0.62, 95% confidenceinterval [CI] 0.46 to 0.85, p � 0.003) and cardiovascular mortality (HR 0.56, 95% CI 0.38to 0.84, p � 0.006), with a possible decreased arrhythmic end point (HR 0.39, 95% CI 0.16to 1.006, p � 0.052) than did the patients with SHF. No differences were observed forischemic stroke (HR 1.08, 95% CI 0.48 to 2.39, p � 0.86), rehospitalization (HR 0.89, 95%CI 0.75 to 1.07, p � 0.24), or progression to New York Heart Association class III-IV (oddsratio 0.80, 95% CI 0.42 to 1.54, p � 0.522). In conclusion, although patients with HF-PEF havebetter mortality outcomes than those with SHF, the morbidity appears to be similar. © 2011

Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:1283–1288)

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Atrial fibrillation (AF) and heart failure (HF) are patho-physiologically intertwined and co-exist in a large percent-age of patients.1 HF is known to be associated with poorutcomes in those with AF. HF is classified as “heart failureith preserved ejection fraction” (HF-PEF) or systolic HF

SHF). Evidence of HF in patient with an ejection fractionEF) �50% is sufficient for a HF-PEF diagnosis, and theiastolic parameters only help to confirm the diagnosis.2

Most previous studies have involved patients with SHF andAF. Risk stratification schemes for stroke (including thecommonly used CHADS2 score [congestive heart failure(CHF) history, hypertension history, age �75 years, diabe-tes mellitus history, stroke symptoms previously or transientischemic attack]) take into account either a history of HF ordepressed EF.3–6 It is unclear whether HF-PEF is associated

aDepartment of Internal Medicine and bDivision of Cardiology (Elec-trophysiology), Wayne State University School of Medicine, Detroit,Michigan. Manuscript received April 10, 2011; manuscript received andaccepted June 9, 2011.

None of the study authors are associated with the National Heart, Lung,and Blood Institute or the Atrial Fibrillation Follow-up Investigation ofRhythm Management trial.

All authors had access to the data and were involved in the conception,data analysis, and writing of the manuscript.

Part of the study results were presented as a poster at the ThirtiethAnnual Scientific Sessions of the Heart Rhythm Society, Boston, Massa-chusetts, May 2009.

*Corresponding author: Tel: 313-745-2647; fax: 313-993-8627.

E-mail address: jacobsony@yahoo.com (S. Jacob).

0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved.doi:10.1016/j.amjcard.2011.06.045

ith similar adverse outcomes (i.e., mortality, stroke risk,leeding risk, and hospitalization risk) in patients with AFompared to those with SHF.7–11 These are important clin-cal considerations, because the prevalence of HF-PEF hasncreased during the past decade,12 and, more significantly,

HF-PEF also accounts for 40% to 50% of patients with AFand HF.8–10 The risk of morbidity and mortality attributableto AF is possibly greater in patients with HF-PEF than inthose with SHF.10 We assessed the prognostic significancef HF-PEF in an AF population compared to an SHF pop-lation.

ethods

We performed a post hoc analysis of the Atrial Fibrilla-ion Follow-up Investigation of Rhythm Management (AF-IRM) trial. This was performed using a publicly available

imited-access data set from the National Heart, Lung andlood Institute, after expedited institutional review boardpproval from Wayne State University (Detroit, Michigan).he limited-access data set was devoid of all patient iden-

ifiers. All authors had full access to all the data in theresent study and take responsibility for the integrity of theata and accuracy of the data analysis.

The details of the AFFIRM study have been previouslyescribed.13–16 In brief, the AFFIRM study was one of the

largest studies of patients with AF who are at risk of strokeor death. The patients were randomized to rate control(n � 2,027) versus rhythm control (n � 2,033) groups. The

study cohort consisted of 722 patients with HF with AF who

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had documented echocardiographic EF17 (Figure 1). Ofthose 722 patients, 320 were in the HF-PEF group (EF�50%) and 402 patients were in the SHF group (EF�50%). The end points of the analyses included all-causemortality, cardiovascular mortality, and ischemic stroke.Rehospitalization was taken as the first hospital admissionsince enrollment. New York Heart Association (NYHA)progression was considered from class I�II at baseline toclass III-IV at the last follow-up point.

The other end points analyzed included an “arrhythmicend point” and a “combined end point.” The “arrhythmicend point” included sustained ventricular tachycardia, tor-sades de pointes, and resuscitated cardiac arrest. The “com-bined end point” was a composite of death, ventriculartachycardia, ventricular fibrillation, cardiac arrest, ischemicstroke, major bleeding, systemic embolism, pulmonary em-bolism, and myocardial infarction. The definition of majorbleeding included both intracranial (intraparenchymal, sub-dural, or subarachnoid) and extracranial (�2 U blood trans-fusion, intensive care unit admission, and/or discontinuationof anticoagulant or antiplatelet therapy) hemorrhage.15 Allatal events, arrhythmic events, and the causes of death wereeviewed by an events committee. A separate committeessessed all cerebrovascular and embolic events.15 The in-ormation reviewed included the paramedic and emergencyoom notes, admission records, hospital progress notes, dis-harge summaries, operative notes, pathology reports, lab-ratory tests, electrocardiographic findings, and a detailedetter from the principal investigator.15

Continuous variables were compared using Student’s ttests and categorical variables using chi-square tests (Table1). Cox proportional hazard regression analysis was per-formed using various end points as the dependent variables.A multivariate model was used for each end point compris-ing all risk factors having a univariate p value of �0.20.Certain previously known risk factors (e.g., gender, hyper-tension) were forced into the model, regardless of the uni-variate p value; p �0.05 was considered statistically signif-icant and used for additional stepwise selection (Table 2).

Figure 1. Cohort selection flowchart.

Kaplan-Meier survival estimates were obtained to estimate

the univariate risk of various end points among the SHF andHF-PEF groups. The CHADS2 score was calculated for all

Table 1Baseline characteristics

Characteristic SHF(n � 402)

HF-PEF(n � 320)

p Value

Age (years) 68.2 � 9 71.3 � 8 �0.0001Atrial fibrillation duration

(years)3.2 � 1 3.1 � 1.1 0.22

New York HeartAssociation class �1

38% 24% �0.0001

Treatment arm (ratecontrol)

49% 52% 0.40

Male gender 74% 49% �0.0001Coronary artery disease* 62% 52% 0.01Left atrial dimension

(mm)4.63 � 0.56 4.46 � 0.61 0.0008

Mitral regurgitation 39% 29% 0.005Hypertension 70% 80% 0.002Peripheral vascular

disease11% 12% 0.59

Diabetes mellitus 29% 28% 0.77Hepatic or renal disease 9% 10% 0.80Pulmonary disease 23% 20% 0.23Smoker 22% 11% �0.0001Stroke 11% 16% 0.04Myocardial infarction 40% 21% �0.01Coronary artery bypass

surgery25% 15% 0.002

Percutaneous coronaryintervention

12% 10% 0.41

Pacemaker 8% 9% 0.80First episode of atrial

fibrillation48% 42% 0.01

Antiarrhythmic drugfailure

13% 17% 0.16

Sinus rhythm atrandomization

47% 50% 0.38

Digoxin 76% 64% 0.001Diuretic 83% 79% 0.31� Blocker 37% 44% 0.06Angiotensin-converting

enzyme inhibitor77% 51% �0.01

Calcium channel blocker 30% 41% 0.003Lipid-lowering therapy 23% 21% 0.41Amiodarone† 36% 26% 0.01Sotalol† 11% 24% �0.01

spirin 27% 26% 0.65Warfarin 90% 89% 0.75International normalized

ratio at baseline2.32 � 0.7 2.23 � 0.7 0.12

CHADS2‡ score 2.46 � 1.07 2.77 � 1.05 0.001CHADS2§ score 2.46 � 1.07 1.89 � 1.03 �0.01

ody mass index (kg/m2) 29.3 � 6.7 29.9 � 6.4 0.28

Data are presented as %, except for continuous variables, which arepresented as mean � SD.

* Included patients with angina, myocardial infarction, history of revas-cularization, atherectomy, stent, or other interventional procedures forischemia.

† Total n � 539; data missing for 183 patients.‡ CHADS2 score calculated with HF-PEF given 1 point for CHF.§ CHADS2 score calculated with HF-PEF not given 1 point for CHF.

patients using established norms.6 The patients were as-

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1285Heart Failure/Heart Failure and Atrial Fibrillation

signed points for a history of CHF (score 1; irrespective ofwhether it was HF-PEF or SHF), hypertension (score of 1),age �75 years (score of 1), diabetes mellitus (score of 1),and stroke symptoms (including transient ischemic attack orsystemic embolism; score of 2). SAS, version 9.1, statisticalsoftware (SAS, Cary, North Carolina) was used to performthe statistical analysis, and Statistical Package for SocialSciences, version 17, software (SPSS, Chicago, Illinois)was used to plot the graphs.

Results

Of the 4,060 patients with AF in the AFFIRM study, 320(7.8%) had echocardiographically proven HF-PEF (Figure1), and HF-PEF accounted for 44.3% of patients with HFand AF (n � 722). In general, the patients with AF andHF-PEF were older, more likely to be female, and to havehypertension and demonstrated a lower prevalence of hy-perlipidemia, smoking, coronary artery disease, and myo-cardial infarction. Calcium channel blocker use and angio-tensin-converting enzyme inhibitors was more prevalent inthose with HF-PEF and SHF, respectively. The mean

Figure 2. HF-PEF versus SHF for outcomes.

Table 2Multivariate and univariate hazard ratios (HRs) for predictors of all-cause mortality

Variable HR 95% CI p Value

Heart failure with preservedejection fraction

0.62 0.46–0.85 0.003

Age 1.05 1.03–1.07 �0.001Coronary artery disease 1.68 1.21–2.32 0.002Smoking 1.61 1.09–2.36 0.02Stroke 1.86 1.29–2.69 0.0008Mitral regurgitation 1.38 1.03–1.86 0.03

Also adjusted for use of angiotensin-converting enzyme inhibitors, �blockers, calcium channel blockers, digoxin, randomization arm, durationof atrial fibrillation, New York Heart Association class at baseline, diabe-tes, hypertension, gender, and rhythm at randomization.

CHADS2 score in the HF-PEF group was greater than in the

SHF group (2.77 vs 2.46, p � 0.001) if 1 point was assignedor CHF. In contrast, the mean CHADS2 score in the HF-EF group was significantly lower than in the SHF group1.89 vs 2.46, p � 0.001) if no point was given for CHF in

the HF-PEF group. The patients with AF and HF-PEF hadsmaller left atrial diameters and a lower prevalence of mitralinsufficiency (Table 1). Anticoagulation use and the use ofrhythm control were similar in both groups.

A total of 666 patients in the entire AFFIRM studypopulation died. A history of HF was associated with a2.7-fold increased risk of mortality (95% confidence inter-val [CI] 2.32 to 3.16, p �0.001) on univariate analysis forthe entire AFFIRM cohort. HF-PEF was also associatedwith a 2.35-fold greater risk of mortality (95% CI 1.99 to

Figure 3. Kaplan-Meier (K-M) curves for all-cause mortality for HF-PEFversus SHF.

Figure 4. Kaplan-Meier (K-M) curves for cardiovascular mortality forHF-PEF versus SHF.

2.76, p �0.001) than those with AF without HF on univar-

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1286 The American Journal of Cardiology (www.ajconline.org)

iate analysis. The mean follow-up duration of our cohort(n � 722) was 3.4 years, with 215 deaths. The SHF grouphad 138 deaths (34%), with 77 deaths (24%) in the HF-PEFgroup. On multivariate analysis, HF-PEF was associatedwith a significantly decreased risk of death (hazard ratio[HR] 0.62, 95% CI 0.46 to 0.85, p � 0.003), cardiovascularmortality (HR 0.56, 95% CI 0.38 to 0.84, p � 0.006), andcombined end point (HR 0.65, 95% CI 0.51 to 0.84, p �0.001), along with a nonsignificant decrease in the arrhyth-mic end point (HR 0.39, 95% CI 0.16 to 1.006, p � 0.052).No difference was found in the rate of major bleeding (HR0.78, 95% CI 0.47 to 1.30, p � 0.33), rehospitalizationHR 0.89, 95% CI 0.75 to 1.07, p � 0.24), incident stroke

Figure 5. Kaplan-Meier (K-M) curves for combined end point for HF-PEFversus SHF.

Figure 6. Kaplan-Meier (K-M) curves for rehospitalization for HF-PEFversus SHF.

HR 1.08, 95% CI 0.48 to 2.39, p � 0.86), and NYHA s

rogression to class III-IV (odds ratio 0.80, 95% CI 0.42 to.54, p � 0.52) between the 2 groups (Figures 2 to 6). The

stroke at baseline was more prevalent in the HF-PEF group(16.2% versus 10.9%, p � 0.04). The incidence of ischemicstroke during follow-up was relatively low in the studycohort (13 events in each group), and warfarin use was theonly significant predictor (HR 0.27, 95% CI 0.11 to 0.64,p � 0.003) and was protective.

Discussion

The independent association of a history of HF and leftventricular systolic dysfunction with poor outcomes in pa-tients with AF has been demonstrated in numerous studies,including the AFFIRM trial.6,15 Despite this, it is unclearwhether AF leads to poor outcomes in patients with HF ingeneral or patients with HF-PEF in particular.9,10,18 Wewere unable to address the latter question, because our studysubset was an all-AF cohort and did not include patientswithout AF. In contrast, our investigation attempted to ex-plore the interaction between left ventricular function (witha special emphasis toward HF-PEF) on the outcomes inpatients with AF and CHF. We have demonstrated thefollowing important findings. First, HF-PEF commonly co-existed with AF in the AFFIRM population (although this isnot reflective of the general AF population). Second, HF-PEF is associated with lower all-cause mortality and car-diovascular mortality and combined end point compared toSHF in patients with AF. Third, arrhythmic risk showed atrend toward being lower among the patients with HF-PEF.Finally, major bleeding, rehospitalization, NYHA progres-sion, and ischemic stroke were all similar for HF-PEF andSHF with effective anticoagulation.

The demographic and medication differences betweenthe HF-PEF and SHF groups at baseline were similar tothose in previous studies.9,11 The prevalence of HF-PEF inur cohort was also in accordance with previous reportsnvolving HF.19 Our study has extended these observationso an AF cohort with HF.8 In a previous study, Fung et al9

observed that patients with AF and HF-PEF had a greatermean left ventricular mass (313.8 vs 220.9 g) and requiredlower doses of furosemide (27.2 vs 41.2 mg) compared topatients with AF and SHF.9 Quality of life, exercise capac-ty, and left ventricular diastolic dysfunction were similarmong the 2 groups.9 However, the study was cross sec-

tional and lacked follow-up data.In contrast to our results, Parkash et al8 found no differ-

nce in survival between AF and HF-PEF and AF and SHF50% vs 48%, p � NS) at 5 years. These differences couldossibly be attributed to our larger sample size (n � 722 vs78) and increased warfarin use (89% vs 77%).8 TheYHA class has been shown to be a strong predictor ofortality, irrespective of the EF.20 Parkash et al21 lacked

ata regarding the NYHA class and investigated acutelyecompensated hospitalized patients at a single medicalenter. Our cohort consisted of stable outpatients beingollowed up at multiple centers and included data on theYHA class.21 Hence, our results bear more similarity to

he Candesartan in Heart Failure Assessment of Reductionn Mortality and Morbidity (CHARM) analysis, which

howed that patients with SHF and AF had the greatest

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1287Heart Failure/Heart Failure and Atrial Fibrillation

mortality in the entire study (more than did patients withHF-PEF and AF).10 Studies involving non-AF cohorts (e.g.,

ramingham and Cardiovascular Health Studies) have alsohown similar results.19 In our study, cardiovascular mor-

tality was less in the patients with HF-PEF, with a nearsignificant trend toward decreased arrhythmia. Our findingsare in concordance with the results from patients with HF-PEF from the Irbesartan in Heart Failure With PreservedEjection Fraction Study (I-Preserve) trial.22

Smith et al11 in a provocative prospective study involv-ng 413 patients with HF showed that after controlling foraseline differences, no difference was observed for hospi-al readmissions among those with HF-PEF and those withHF.11 We also found HF-PEF to be associated with similar

morbidity and progression to decompensated NYHA classduring follow-up as SHF. We also report the lack of differ-ences among patients with AF and HF-PEF and SHF formajor bleeding episodes. CHF has been associated with anincreased bleeding risk.14 Amiodarone also interacts with

arfarin and requires warfarin dose adjustment. Amioda-one use was significantly greater among the patients withHF in our group; however, the bleeding risk was similar to

hat in the HF-PEF group. This could possibly be due toetter physician awareness and close follow-up; however,uture studies involving a larger number of events areeeded.14

Although most of the stroke risk stratification schemesfor patients with AF involve a history of HF as a predic-tor,3,5,6,23 some do not include echocardiographic data onleft ventricular function.6,24,25 Schemes that incorporateechocardiographic data,3,5,26,27 only address patients withdepressed EF. None of these schemes have specificallyaddressed the stroke risk in patients with HF-PEF. Wereport 3 interesting observations regarding stroke in patientswith AF and HF-PEF. First, these patients had an increasedhistory of stroke at baseline (16.2% vs 10.9%, p � 0.04)ompared to patients with AF and SHF. Second, the meanHADS2 score was also greater in the HF-PEF group ataseline compared to the SHF group (if HF-PEF was givenpoint as SHF). Finally, no difference was found in the

ncidence of stroke in HF-PEF and SHF groups once effec-ively anticoagulated. The stroke risk in the patients withF-PEF should be intuitively greater secondary to increasedypertension, age, and history of stroke at baseline.3–6

However, this could be partially negated by the increasedstroke risk with depressed ventricular function.3–6 TheCHARM investigators have also showed that the stroke riskfrom AF was similar in both HF-PEF and SHF groups.10

The lack of difference and low event rates (26 strokes intotal) in our study could be have resulted from the greateruse of anticoagulation (close to 90%). This would be ex-pected in any conventional cohort receiving optimal ther-apy. We hope to throw light on the neglected question ofstroke risk in those with AF and HF-PEF.

Our study had the same limitations as those of anyretrospective analysis. Although the AFFIRM populationwas a fair representation of patients with AF in the com-munity, our findings are only hypothesis generating and donot change contemporary management. We also did nothave echocardiographic data for all the AFFIRM patients

with CHF. However, these excluded patients shared char-

acteristics similar to those of the analyzed cohort. Also,significant baseline differences were present between theHF-PEF and SHF groups that could have acted as confound-ers. We also lacked information regarding diastolic dys-function, which has been shown to be a prognosticator ofAF outcomes.28 However, Fung et al,9 in a cohort similar tours, showed no differences in the severity of diastolicysfunction among those with AF and HF-PEF versus thoseith AF and SHF. Our definition of HF-PEF was similar to

hat used in previous studies.2,19,29 We also performed aseparate analysis in which the HF-PEF group included thosewith CHF and EF �40% (instead of EF �50% to excludebias from possibly clinically nonsignificant systolic dys-function) and for rate versus rhythm control. The findingsfrom these analyses were not significant and are not pre-sented. In conclusion, although patients with HF-PEF havebetter mortality outcomes than those with SHF, the morbid-ity appears to be similar.

1. Jacob S, Ali OA, Pidlaoan V, Badheka AO, Kerin NZ. Pharmacother-apy of atrial fibrillation: a pathophysiological perspective and review.Am J Ther 2011;18:241–260.

2. Zile MR, Gaasch WH, Carroll JD, Feldman MD, Aurigemma GP,Schaer GL, Ghali JK, Liebson PR. Heart failure with a normal ejectionfraction: is measurement of diastolic function necessary to make thediagnosis of diastolic heart failure? Circulation 2001;104:779–782.

3. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, EllenbogenKA, Halperin JL, Kay GN, Le Huezey JY, Lowe JE, Olsson SB,Prystowsky EN, Tamargo JL, Wann LS. 2011 ACCF/AHA/HRS Fo-cused Updates Incorporated Into the ACC/AHA/ESC 2006 Guidelinesfor the Management of Patients with Atrial Fibrillation: a report of theAmerican College of Cardiology Foundation/American Heart Associ-ation Task Force on Practice Guidelines Developed in partnership withthe European Society of Cardiology and in collaboration with theEuropean Heart Rhythm Association and the Heart Rhythm Society.J Am Coll Cardiol 2011;57:e101–e198.

4. The SPAF III Writing Committee for the Stroke Prevention in AtrialFibrillation Investigators. Patients with nonvalvular atrial fibrillation atlow risk of stroke during treatment with aspirin: Stroke Prevention inAtrial Fibrillation III Study. JAMA 1998;279:1273–1277.

5. Singer DE, Albers GW, Dalen JE, Fang MC, Go AS, Halperin JL, LipGY, Manning WJ. Antithrombotic therapy in atrial fibrillation: Amer-ican College of Chest Physicians Evidence-Based Clinical PracticeGuidelines (8th edition). Chest 2008;133:546S–592S.

6. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Rad-ford MJ. Validation of clinical classification schemes for predictingstroke: results from the National Registry of Atrial Fibrillation. JAMA2001;285:2864–2870.

7. McDermott MM, Feinglass J, Lee PI, Mehta S, Schmitt B, Lefevre F,Gheorghiade M. Systolic function, readmission rates, and survivalamong consecutively hospitalized patients with congestive heart fail-ure. Am Heart J 1997;134:728–736.

8. Parkash R, Maisel WH, Toca FM, Stevenson WG. Atrial fibrillation inheart failure: high mortality risk even if ventricular function is pre-served. Am Heart J 2005;150:701–706.

9. Fung JW, Sanderson JE, Yip GW, Zhang Q, Yu CM. Impact of atrialfibrillation in heart failure with normal ejection fraction: a clinical andechocardiographic study. J Card Fail 2007;13:649–655.

10. Olsson LG, Swedberg K, Ducharme A, Granger CB, Michelson EL,McMurray JJ, Puu M, Yusuf S, Pfeffer MA; CHARM Investigator-s.Atrial fibrillation and risk of clinical events in chronic heart failurewith and without left ventricular systolic dysfunction: results from theCandesartan in Heart Failure-Assessment of Reduction in Mortalityand morbidity (CHARM) program. J Am Coll Cardiol 2006;47:1997–2004.

11. Smith GL, Masoudi FA, Vaccarino V, Radford MJ, Krumholz HM.Outcomes in heart failure patients with preserved ejection fraction:mortality, readmission, and functional decline. J Am Coll Cardiol

2003;41:1510-1508.

1

1

1288 The American Journal of Cardiology (www.ajconline.org)

12. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, LiuPP. Outcome of heart failure with preserved ejection fraction in apopulation-based study. N Engl J Med 2006;355:260–269.

13. Badheka AO, Rathod A, Kizilbash MA, Garg N, Mohamad T, AfonsoL, Jacob S. Impact of lipid-lowering therapy on outcomes in atrialfibrillation. Am J Cardiol;105:1768–1772.

14. DiMarco JP, Flaker G, Waldo AL, Corley SD, Greene HL, Safford RE,Rosenfeld LE, Mitrani G, Nemeth M; AFFIRM Investigators.Factorsaffecting bleeding risk during anticoagulant therapy in patients withatrial fibrillation: observations from the Atrial Fibrillation Follow-upInvestigation of Rhythm Management (AFFIRM) study. Am Heart J2005;149:650–656.

15. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y,Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, CorleySD; Atrial Fibrillation Follow-up Investigation of Rhythm Manage-ment (AFFIRM) Investigators.A comparison of rate control andrhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–1833.

16. Badheka AO, Rathod A, Kizilbash MA, Garg N, Mohamad T, AfonsoL, Jacob S. Influence of obesity on outcomes in atrial fibrillation: yetanother obesity paradox. Am J Med 2010;123:646–651.

17. Olshansky B, Heller EN, Mitchell LB, Chandler M, Slater W, GreenM, Brodsky M, Barrell P, Greene HL. Are transthoracic echocardio-graphic parameters associated with atrial fibrillation recurrence orstroke? Results from the Atrial Fibrillation Follow-Up Investigation ofRhythm Management (AFFIRM) study. J Am Coll Cardiol 2005;45:2026–2033.

8. Mamas MA, Caldwell JC, Chacko S, Garratt CJ, Fath-Ordoubadi F,Neyses L. A meta-analysis of the prognostic significance of atrialfibrillation in chronic heart failure. Eur J Heart Fail 2009;11:676–683.

9. Somaratne JB, Berry C, McMurray JJ, Poppe KK, Doughty RN,Whalley GA. The prognostic significance of heart failure with pre-

served left ventricular ejection fraction: a literature-based meta-anal-ysis. Eur J Heart Fail 2009;11:855–862.

20. Ahmed A, Aronow WS, Fleg JL. Higher New York Heart Associationclasses and increased mortality and hospitalization in patients withheart failure and preserved left ventricular function. Am Heart J2006;151:444–450.

21. Parkash R, Stevenson WG. Atrial fibrillation and clinical events inchronic heart failure. J Am Coll Cardiol 2007;49:376–377.

22. Zile MR, Gaasch WH, Anand IS, Haass M, Little WC, Miller AB,Lopez-Sendon J, Teerlink JR, White M, McMurray JJ, Komajda M,McKelvie R, Ptaszynska A, Hetzel SJ, Massie BM, Carson PE. Modeof death in patients with heart failure and a preserved ejection fraction:results from the Irbesartan in Heart Failure With Preserved EjectionFraction Study (I-Preserve) trial. Circulation 2010;121:1393–1405.

23. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinicalrisk stratification for predicting stroke and thromboembolism in atrialfibrillation using a novel risk factor-based approach: the euro heartsurvey on atrial fibrillation. Chest 2010;137:263–272.

24. Risk factors for stroke and efficacy of antithrombotic therapy in atrialfibrillation. Analysis of pooled data from five randomized controlledtrials. Arch Intern Med 1994;154:1449–1457.

25. Wang TJ, Massaro JM, Levy D, Vasan RS, Wolf PA, D’Agostino RB,Larson MG, Kannel WB, Benjamin EJ. A risk score for predictingstroke or death in individuals with new-onset atrial fibrillation in thecommunity: the Framingham Heart Study. JAMA 2003;290:1049–1056.

26. Echocardiographic predictors of stroke in patients with atrial fibrilla-tion: a prospective study of 1066 patients from 3 clinical trials. ArchIntern Med 1998;158:1316–1320.

27. Investigators SPiAF. Risk factors for thromboembolism during aspirintherapy in patients with atrial fibrillation: the Stroke Prevention inAtrial Fibrillation study. J Stroke Cerebrovasc Dis 1995;5:147–157.

28. Okura H, Takada Y, Kubo T, Iwata K, Mizoguchi S, Taguchi H, TodaI, Yoshikawa J, Yoshida K. Tissue Doppler-derived index of leftventricular filling pressure, e/E=, predicts survival of patients withnon-valvular atrial fibrillation. Heart 2006;92:1248–1252.

29. Vasan RS, Levy D. Defining diastolic heart failure: a call for stan-dardized diagnostic criteria. Circulation 2000;101:2118–2121.